Tetrahydroisoquinolin-1-one derivative or salt thereof

ABSTRACT

To provide a pharmaceutical, in particular a compound which can be used as a therapeutic agent for irritable bowel syndrome (IBS). It was found that a tetrahydroisoquinolin-1-one derivative having an amide group at the 4-position or a pharmaceutically acceptable salt thereof has an excellent bombesin 2 (BB2) receptor antagonistic action. It is also found that the tetrahydroisoquinolin-1-one derivative is highly effective on bowel movement disorders. From the above, the tetrahydroisoquinolin-1-one derivative of the present invention is useful as a therapeutic agent for diseases associated with a BB2 receptor, in particular IBS.

This application is a Divisional of U.S. patent application Ser. No.13/942,158, filed Jul. 15, 2013, which is a Divisional of U.S. patentapplication Ser. No. 12/600,894, filed Nov. 19, 2009, which is the U.S.National Phase of PCT/JP2008/059621, filed Mar. 26, 2008, which claimspriority from Japanese Patent Application No. P2007-140097, filed May28, 2007, all of which are incorporated herein by reference in entirety.

TECHNICAL FIELD

The present invention relates to a pharmaceutical, in particular, atetrahydroisoquinolin-1-one derivative or a salt thereof, which isuseful as a therapeutic agent for irritable bowel syndrome.

BACKGROUND ART

Irritable bowel syndrome (IBS) is a syndrome which causes chronicsymptoms such as abdominal pain, bloating, and the like, bowel movementdisorders such as diarrhea, constipation, and the like, defecationtrouble, defecation straining, and the like. It is caused by functionalabnormality of the lower digestive tract, mainly the large intestine,despite the absence of organic disorders such as inflammation, tumors,and the like, and is classified based on the conditions of stool intodiarrhea-predominant, constipation-predominant, and alternating IBSwhich alternately repeats diarrhea and constipation. IBS is a diseasewhich has a relatively high frequency occupying from 20 to 50% of boweldisease patients who consult outpatient cares, which is predominant infemales with a male to female ratio of 1:2 regardless of race, and whichhas a high prevalence rate in the younger generation. Since mentalstress correlates strongly with the state of the disease, it is regardedas a representative stress-related somatic disease and it is said thatthe stress management is important for the improvement of symptoms.Actually, it is known that abnormal motility of gastrointestinal tractis significantly accelerated and the symptoms are aggravated whenemotional stress is applied to IBS patients. In addition, since thesymptoms continue, a vicious circle is likely to form in which increasedpatient anxiety further aggravates the symptoms.

As the drug therapy of IBS, an anticholinergic is used for abdominalpain, and a tricyclic antidepressant for the improvement of painthreshold value reduction in the digestive tracts, and for theimprovement of abnormal bowel motility, a stegnotic, a drug forcontrolling intestinal function, and the like in the case of diarrhea,and a saline cathartic and the like in the case of constipation, howeverthese are merely symptomatic therapies and their effects are not clear.As an agent from which effects can be expected for both diarrhea andconstipation, there is polycarbophil calcium, which regulates thehardness of feces by gelating in the intestines, however it exerts verylimited effects because not only there is a bloating at the initialstage of its administration but also it requires time to exhibit theeffects. Anxiolytics and antidepressants are used when anxiety andtension are considerably increased due to stress, however they areadministered at a dose lower than the dose in the psychiatric field, sothat there are cases in which the mental symptoms are not improved orcases in which these are improved but they do not exhibit any effects onthe bowel movement disorder. Generally, among the symptoms of IBS,anxiolytics are effective for diarrhea and abdominal pain in some cases,but they have a tendency to exhibit little effect on constipation.

There are a 5-HT3 receptor antagonist alosetron and a 5-HT4 receptoragonist tegaserod as the agents, which have been drawing attention inrecent years, and they are used in the diarrhea-predominant and theconstipation-predominant, respectively. These agents improve the bowelmovement by regulating the movement of intestines, and exhibit an effectquickly. However, though alosetron shows a relatively high improvingrate of from 40 to 60% for abdominal symptoms and diarrhea, constipationoccurs in 30 to 35% of the patients and it causes ischemic colitis(including mortal cases) as a serious side effect, so that its use islimited (Non-Patent Document 1). In addition, it cannot be said that theeffect of tegaserod on the constipation-predominant is sufficient, andthere is a possibility of causing tachyphylaxis (a phenomenon in whichresistance is generated when a drug is repeatedly administered within ashort period of time).

Apropos, when the living body receives a stress, it generates ahypothalamic-pituitary-adrenal system (HPA system) reaction, in which anadrenocorticotropic hormone (ACTH) is released through the secretion ofa stress-related substance from the hypothalamus and a subsequent actionupon the anterior hypophysis, and the ACTH released into the bloodsecretes corticosterone from the adrenal cortex, and thereby showsvarious stress responses such as increase in the blood pressure and thelike. As the stress-related substance, corticotropin releasing hormone(CRH), bombesin (BB)/gastrin releasing peptide (GRP), vasopressin,neuropeptide Y, substance P, neurotensin, and the like are known.Secretion of these substances from the hypothalamus is accelerated whena stress is applied to an animal. Particularly regarding the CRH, it hasbeen reported that it reinforces ACTH release and large bowel movementwhen administered to IBS patients (Non-Patent Document 2).

The bombesin/GRP as one of the stress-related substances is a brain-gutpeptide and expresses various physiological actions via bombesinreceptors. The bombesin receptor is classified into 3 subtypes of BB1,BB2 and BB3/BRS3 (bombesin receptor subtype-3), and as intrinsic ligandsof mammals for the BB1 and BB2 receptors, neuromedin B and GRP have beenidentified respectively. It has been reported that the GRP and BB2receptors are present ubiquitously in the brain, the digestive tracts,and the like, but GRP is markedly increased in the amygdala andhypothalamus when stress is applied to an animal (Non-Patent Document3). In addition, it has been reported also that a BB2 receptorantagonist inhibits the increase in ACTH when administered into thecerebral ventricle in a restraint stress-added rat (Non-Patent Document4).

As the role of the GRP/BB2 receptor in the digestive tract functions, ithas been reported that it enhances the contraction in isolated human andrabbit ileum longitudinal muscle specimens (Non-Patent Documents 5 and6), and enhances the water secretion in guinea pigs with the coexistenceof a vasoactive intestinal peptide (VIP) (Non-Patent Document 7). Inaddition, it has been reported that BB2 receptor antagonists includingRC-3095 that is a peptidic BB2 receptor antagonist, is effective for anabnormal bowel motility in a stress-induced defecation model. It hasalso been reported that, using an abdominal muscle contraction reactionas the index, RC-3095 is effective for an abdominal symptom in anabdominal pain model induced by large intestinal distension. Accordinglythe BB2 receptor antagonist shows excellent efficacy on both theabdominal symptom and abnormal bowel motility (Patent Document 1).

As shown above, the BB2 receptor antagonist is expected to be atherapeutic agent for IBS, showing excellent efficacy on both theabdominal symptom and abnormal bowel motility.

Furthermore, since the bombesin/GRP also has a function as a cell growthfactor and the expression of the GRP/BB2 receptor is increased invarious cancer cells of lung cancer, prostate cancer, and the like, theefficacy of RC-3095 has been reported in a large number of antitumortests (Non-Patent Documents 8 to 10). From this viewpoint, the BB2receptor antagonist can also be expected to be effective against variouscancers.

The tetrahydroisoquinolin-1-one derivative has been reported in PatentDocuments 2 to 4.

Patent Document 2 describes that a 3,4-dihydroisoquinolin-1-onederivative represented by the following formula (A) has a caspaseactivating action and an apoptosis inducing action, and is effective forcancers, autoimmune diseases, rheumatoid arthritis, inflammatory bowelsyndrome, psoriasis, and the like. However, there is no description ofits antagonistic action on a bombesin type 2 receptor or of its efficacyregarding IBS.

(for the symbols in the formula, refer to the publication)

Patent Document 3 describes that a tetrahydroisoquinolin-1-onederivative represented by the following formula (B) is a ligand of anHDM2 protein, has an apoptosis inducing activity and a proliferationinhibitory activity, and is effective against cancers. However, there isno description of its antagonistic action on a bombesin type 2 receptoror of its efficacy regarding IBS.

(for the symbols in the formula, refer to the publication)

Patent Document 4 describes that a tetrahydroisoquinolin-1-onederivative represented by the following formula (C) is a neurotensin-2(NT-2) receptor antagonist and is effective against pain. However, forR⁵ corresponding to R¹ of the present invention, there is no descriptionon the R¹ group of the present invention. In addition, there is nodescription of its antagonistic action on a bombesin type 2 receptor orof its efficacy regarding IBS.

(wherein R⁵ means (C₁-C₈) alkyl which is optionally substituted with agroup selected from trifluoromethyl, halogen, saturated or partiallyunsaturated (C₃-C₈) cycloalkyl, and (C₆-C₁₀) aryl. For the othersymbols, refer to the publication.)

The compounds described in the following Tables 1 to 11 below arereported as Catalog Compounds. However, there is no description of theantagonistic action on a bombesin type 2 receptor and the efficacy forIBS, of these compounds. Further, in the following Tables, theabbreviations below are used. Me: Methyl, Et: Ethyl, iPr: Isopropyl,nBu: Normal Butyl, Ph: Phenyl.

TABLE 1

CAS Registry No. R^(a)R^(b)N— 931939-66-1

931315-65-0

902607-43-6 Me₂N— 902450-09-3 Ph—(CH₂)₂—NH— 891914-00-4 PhCH₂—NH—891913-84-1

891913-76-1

891913-68-1

891913-28-3

891913-04-5

891912-88-2 EtNH— 891912-80-4

TABLE 2 891912-64-4

891912-56-4

891912-48-4

891912-40-6

891912-16-6

891912-08-6

891912-00-8

891911-84-5

891911-60-7

891911-52-7

891911-44-7

891911-36-7

TABLE 3 891911-29-8

891911-22-1

891911-07-2

891910-93-3

891910-86-4

891910-72-8

891910-65-9

891910-58-0

891910-23-9

891910-07-9

891909-99-2

891909-91-4 EtO—(CH₂)₃—NH— 891909-83-4

TABLE 4 891909-75-4

891909-67-4

891909-59-4 iPrO—(CH₂)₃—NH— 891909-51-6

891909-27-6 PhN(Et)—(CH₂)₃—NH— 891909-11-8

891909-03-8

891908-95-5

891908-55-7 Et₂N— 891907-99-6

891907-91-8

891907-83-8

891907-75-8

891907-43-0 MeO—(CH₂)₃—NH— 891907-35-0 nBuNH— 891907-27-0 iPrNH—891907-19-0

891907-11-2 MeO—(CH₂)₂—NH—

TABLE 5 891907-03-2

891906-95-9

891906-87-9

891906-79-9

891906-71-1

891906-55-1

891906-39-1

891905-75-2

891904-87-3

TABLE 6

CAS Registry No. R^(a)R^(b)N— 685520-62-1

685520-61-0

442858-62-0 EtO₂C—CH₂—NH— 442858-61-9

442858-27-7 MeO₂C—(CH₃)₂—NH— 442858-05-1 MeO₂C—CH₂—NH— 442858-04-0

442857-76-3

442857-73-0

442856-86-2

442856-85-1

442856-80-6 Et₂N—

TABLE 7 442856-71-5

442856-34-0

442856-31-7

442856-30-6

442856-29-3 iPrNH— 442856-28-2

442856-17-9

442856-15-7 PhN(Et)—(CH₂)₃—NH— 442855-08-5

442854-93-5

442854-92-4

442854-57-1 MeO—(CH₂)₂—NH— 442854-41-3

TABLE 8

CAS Registry No. R^(a)R^(b)N— 685520-63-2

442859-46-3

442859-42-9

442859-40-7

442859-39-4

442859-38-3

442859-36-1

442859-27-0

442859-26-9

TABLE 9 442859-25-8

442859-20-3 Et₂N— 442859-13-4

442859-12-3

442859-11-2 MeO—(CH₂)₃—NH— 442859-09-8 nBuN(Et)— 442859-06-5

442859-05-4 nBuNH— 442859-03-2

442859-02-1 EtO₂C—CH₂—NH— 442859-01-0 MeO—(CH₂)₂—NH— 442858-99-3nBuN(Me)NH— 442858-98-2

442858-93-7

442858-91-5 PhCH₂N(Me)— 442858-86-8

442858-79-9

TABLE 10 442858-77-7

442858-76-6

442858-72-2

442858-67-5

442858-56-2 iPrNH— 442858-55-1

TABLE 11

CAS Registry No. R^(a)R^(b)N— 442888-72-4

442888-70-2

442888-60-0

442888-49-5

442888-41-7

442888-39-3

442888-37-1

442888-35-9

Non-Patent Document 1: “American Journal of Gastroenterology”, (USA),2003, vol. 98, p. 750-758

Non-Patent Document 2: “Gut”, (England), 1998, vol. 42, p. 845-849

Non-Patent Document 3: “The Journal of Neuroscience”, (USA), 1998, vol.18, p. 4758-4766

Non-Patent Document 4: “Life Sciences”, (Holland), 2002, vol. 70, p.2953-2966

Non-Patent Document 5: “Gastroenterology”, (USA), 1991, vol. 100, p.980-985

Non-Patent Document 6: “Neurogastroenterology and Motility”, (England),1997, vol. 9, p. 265-270

Non-Patent Document 7: “Annals of the New York Academy of Science”,(USA), 2000, vol. 921, p. 420-424

Non-Patent Document 8: “Cancer”, (USA), 1998, vol. 83, p. 1335-1343

Non-Patent Document 9: “British Journal of Cancer”, 2000, vol. 83, p.906-913,

Non-Patent Document 10: “Cancer”, (USA), 2000, vol. 88, p. 1384-1392

Patent Document 1: Pamphlet of International Publication No. 2006/115135

Patent Document 2: Pamphlet of International Publication No. 2004/04727

Patent Document 3: Pamphlet of International Publication No. 2006/97323

Patent Document 4: Pamphlet of International Publication No. 03/29221

DISCLOSURE OF THE INVENTION Problem that the Invention is to Solve

It is an object of the present invention to provide a novelpharmaceutical having a BB2 receptor antagonistic action, in particular,a novel compound which is useful as a therapeutic agent for IBS.

Means for Solving the Problems

The present inventors have conducted extensive studies on BB2 receptorantagonists, and as a result, we have found that a noveltetrahydroisoquinolin-1-one derivative having an amide group as asubstituent at the 4-position has an excellent BB2 receptor antagonisticaction, thus completing the present invention.

Namely the present invention relates to a tetrahydroisoquinolin-1-onederivative represented by the general formula (I) or a pharmaceuticallyacceptable salt thereof:

[the symbols in the formula represent the following meanings:

R¹: lower alkylene-OH, lower alkylene-N(R⁰)(R⁶), loweralkylene-CO₂R^(o), cycloalkyl, cycloalkenyl, aryl, heterocyclic group,-(lower alkylene substituted with —OR⁰)— aryl or loweralkylene-heterocyclic group,

wherein the lower alkylene, cycloalkyl, cycloalkenyl, aryl andheterocyclic group in R¹ may each be substituted,

R⁰: the same as or different from each other, each representing —H orlower alkyl,

R⁶: R⁰, —C(O)—R⁰, —CO₂-lower alkyl or —S(O)₂-lower alkyl,

R²: lower alkyl, lower alkylene-OR^(o), lower alkylene-aryl, loweralkylene-heterocyclic group, lower alkylene-N(R⁰)CO-aryl, loweralkylene-O-lower alkylene-aryl, —CO₂R^(o), —C(O)N(R⁰)₂, —C(O)N(R⁰)-aryl,—C(O)N(R⁰)-lower alkylene-aryl, aryl or heterocyclic group,

wherein the aryl and heterocyclic group in R² may each be substituted,

R³: —H or lower alkyl,

or R² and R³ may be combined to form C₂₋₆ alkylene,

R⁴: —N(R⁷)(R⁸), —N(R⁰)—OH, —N(R¹⁰)—OR⁷, —N(R⁰)—N(R)(R⁷),—N(R⁰)—S(O)₂-aryl, or —N(R⁰)—S(O)₂—R⁷,

wherein the aryl in R⁴ may be substituted,

R⁷: lower alkyl, halogeno-lower alkyl, lower alkylene-CN, loweralkylene-OR⁰, lower alkylene-CO₂R⁰, lower alkylene-C(O)N(R⁰)₂, loweralkylene-C(O)N(R⁰)N(R⁰)₂, lower alkylene-C(═NH)NH₂, loweralkylene-C(═NOH)NH₂, heteroaryl, lower alkylene-X-aryl, or loweralkylene-X-heterocyclic group,

wherein the lower alkylene, aryl, heteroaryl, and heterocyclic group inR⁷ may each be substituted,

X: single bond, —O—, —C(O)—, —N(R⁰)—, —S(O)_(p)—, or *—C(O)N(R⁰)—,

wherein * in X represents a bond to lower alkylene,

m: an integer of 0 to 3,

p: an integer of 0 to 2,

R⁸: —H or lower alkyl,

or R⁷ and R⁸ may be combined to form lower alkylene-N(R⁹)-loweralkylene, lower alkylene-CH(R⁹)-lower alkylene, loweralkylene-arylene-lower alkylene, or lower alkylene-arylene-C(O)—,

R⁹: aryl and heteroaryl which may each be substituted,

R¹⁰: —H, lower alkyl, or —C(O)R⁰,

R⁵: lower alkyl, halogeno-lower alkyl, halogen, nitro, —OR⁰,—O-halogeno-lower alkyl, —N(R⁰)₂, —O-lower alkylene-CO₂R⁰, or —O-loweralkylene-aryl,

wherein the aryl in R⁵ may be substituted,

provided that, when R⁴ is —N(R⁷)(R⁸),

(1) a compound wherein R¹ is unsubstituted cyclopentyl and R² isunsubstituted 2-thienyl;

(2) a compound wherein R¹ is unsubstituted cyclohexyl and R² is4-methoxyphenyl;

(3) a compound wherein R¹ is 4-methoxyphenyl and R² is 4-methoxyphenyl;and

(4) a compound wherein R¹ is (morpholin-4-yl)ethyl and R² is4-ethoxyphenyl are excluded,

-   furthermore,    2,3-bis(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,-   3-(4-chlorobenzyl)-2-(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,-   3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-furylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,-   3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,-   ethyl    3-{3-[3,5-bis(trifluoromethyl)phenyl]-4-{[2-(4-methoxyphenyl)ethyl]carbamoyl}-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl}propanoate,-   N-benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-1-oxo-2-(tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,-   3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methoxyethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,-   3-[3,5-bis(trifluoromethyl)phenyl]-2-(2-furylmethyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,-   3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-furylmethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,    and-   (4-chlorophenyl)[3-(4-chlorophenyl)-4-[(2-methoxyethyl)carbamoyl]-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]acetic    acid    are excluded.    The symbols hereinafter represent the same meanings].

Further, the present application relates to a pharmaceutical comprisinga tetrahydroisoquinolin-1-one derivative represented by the generalformula (I) or a salt thereof as an active ingredient, in particular aBB2 receptor antagonist, a therapeutic agent for irritable bowelsyndrome or a therapeutic agent for cancers.

Furthermore, the present application relates to the use of the compoundrepresented by the formula (I) or a pharmaceutically acceptable saltthereof for the manufacture of a BB2 receptor antagonist, a therapeuticagent for irritable bowel syndrome, or a therapeutic agent for cancers,and to a method for treating irritable bowel syndrome or cancers,comprising administering to a patient an effective amount of thecompound represented by the formula (I) or a pharmaceutically acceptablesalt thereof

Namely, the present application relates to: (1) a pharmaceuticalcomposition comprising the compound described in the general formula (I)or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier,

(2) the pharmaceutical composition as described in (1), which is a BB2receptor antagonist,

(3) the pharmaceutical composition as described in (1), which is atherapeutic agent for irritable bowel syndrome,

(4) the pharmaceutical composition as described in (1), which is atherapeutic agent for cancers,

(5) use of the compound as described in the general formula (I) or apharmaceutically acceptable salt thereof for the manufacture of a BB2receptor antagonist, a therapeutic agent for irritable bowel syndrome,or a therapeutic agent for cancers, and

(6) a method for treating irritable bowel syndrome or cancers,comprising administering to a patient a therapeutically effective amountof the compound as described in the general formula (I) or apharmaceutically acceptable salt thereof.

Effects of the Invention

The compound of the present invention is useful as a therapeutic agentfor IBS since it has an excellent antagonistic action on a BB2 receptor.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in more detail as follows.

The “lower alkyl” is preferably a linear or branched alkyl having 1 to 6carbon atoms (which is hereinafter simply referred to as C₁₋₆), andspecifically, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group, and the like.More preferably, it is C₁₋₄ alkyl, and more preferably, it includesmethyl, ethyl, n-propyl, and isopropyl.

The “lower alkylene” is preferably a linear or branched C₁₋₆ alkylene,and specifically, it includes methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, propylene,methylmethylene, ethylethylene, 1,2-dimethylethylene,1,1,2,2-tetramethylethylene group, and the like. Preferably, it is C₁₋₄alkylene, and more preferably, it includes methylene, ethylene, andtrimethylene.

The “halogen” means F, Cl, Br, or I.

The“halogeno-lower alkyl” refers to C₁₋₆ alkyl substituted with one ormore halogens. It is preferably lower alkyl substituted with 1 to 5halogens, and more preferably trifluoromethyl.

The “halogeno-lower alkylene” refers to C₁₋₆ alkylene substituted withone or more halogens. It is preferably lower alkylene substituted with 1to 5 halogens, and more preferably, it includes difluoromethylene anddifluoroethylene.

The “cycloalkyl” refers to a C₃₋₁₀ saturated hydrocarbon ring group,which may have a bridge. Specifically, it includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantylgroup, and the like. It is preferably C₃₋₈ cycloalkyl, and morepreferably C₃₋₆ cycloalkyl, and even more preferably, it includescyclopentyl and cyclohexyl.

The “cycloalkenyl” refers to C₃₋₁₅ cycloalkenyl, which may have abridge, and it includes a ring group condensed with a benzene ring at adouble bond site. Specifically, it includes cyclopentenyl,cyclopentadienyl, cyclohexenyl, cyclohexadienyl, 1-tetrahydronaphthyl,1-indenyl, 9-fluorenyl group, and the like. Preferably, it is C₄₋₁₀cycloalkenyl, and more preferably, it includes cyclopentenyl andcyclohexenyl.

The “aryl” refers to a C₆₋₁₄ monocyclic to tricyclic aromatichydrocarbon ring group, and preferably, it includes phenyl and naphthyl,and more preferably phenyl.

The “arylene” refers to a divalent group formed by removing an arbitraryhydrogen atom from aryl, and it is preferably phenylene, and morepreferably orthophenylene.

The “heteroaryl” means a ring group consisting of i) monocyclic 5- to6-membered heteroaryl containing 1 to 4 hetero atoms selected from O, S,and N, and ii) bicyclic a 8- to 10-membered heterocycle and a tricyclic11- to 14-membered heterocycle, each containing 1 to 5 hetero atomsselected from O, S, and N, which are formed by condensation of themonocyclic heteroaryl, and one or two rings selected from the groupconsisting of monocyclic heteroaryl and a benzene ring. The ring atom Sor N may be oxidized to form an oxide or a dioxide.

The “heteroaryl” preferably includes pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl,oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, indolyl, indazolyl,benzoimidazolyl, imidazopyridyl, quinolyl, quinazolyl, quinoxalinyl,naphthylidinyl, benzofuranyl, benzothienyl, benzoxazolyl,benzothiazolyl, and carbazolyl, and more preferably pyrrolyl, pyridyl,furyl, thienyl, and thiazolyl.

The “heterocyclic group” means a ring group consisting of i) amonocyclic 3- to 8-membered (preferably 5- to 7-membered) heterocyclecontaining 1 to 4 hetero atoms selected from O, S, and N, and ii) abicyclic 8- to 14-membered (preferably 9- to 11-membered) heterocycleand a tricyclic 11- to 20-membered (preferably 12- to 15-membered)heterocycle, each containing 1 to 5 hetero atoms selected from O, S, andN, which are formed by the condensation of the monocyclic heterocycle,and one or two rings selected from the group consisting of a monocyclicheterocycle, a benzene ring, C₅₋₈ cycloalkane, and C₅₋₈ cycloalkene. Thering atom S or N may be oxidized to form an oxide or a dioxide, or mayhave a bridge.

The “heterocyclic group” preferably includes aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,homomorpholinyl, tetrahydrothienyl, tetrahydrothiopyranyl,thiomorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, oxadiazolyl,thiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl,imidazopyridyl, quinolyl, quinazolyl, quinoxalinyl, naphthylidinyl,benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl,dihydroindolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl,tetrahydroquinolyl, benzodioxolyl, dihydrobenzodioxynyl,dihydrobenzoxazinyl, tetrahydronaphthylidinyl, carbazolyl, andquinuclidinyl, and more preferably pyrrolidyl, piperidyl,tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, pyridyl, furyl, thienyl,and thiazolyl.

The expression “which may be substituted” means “which is notsubstituted” or “which is substituted with 1 to 5 substituents which maybe the same as or different from each other”. The expression “which issubstituted” refers to “which is substituted with 1 to substituentswhich are the same as or different from each other”. Further, if aplurality of substituents are contained, the substituents may be thesame as or different from each other.

The substituent for the “lower alkylene” which may be substituted in R¹is preferably a group selected from Group G¹, and more preferably —OH orphenyl.

Group G¹: halogen, —OR⁰, —N(R⁰)(R⁶), and aryl.

Provided that, the “aryl” in Group G¹ may be substituted with a groupselected from the group consisting of halogen, lower alkyl,halogeno-lower alkyl, —OR⁰, and —O-halogeno-lower alkyl.

The substituent for the “cycloalkyl”, “cycloalkenyl”, and “heterocyclicgroup” which may be each substituted in R¹ is preferably a groupselected from Group G², more preferably —OR⁰, —CO₂R^(o), —N(R⁰)₂,—N(R⁰)C(O)R^(o), —N(R⁰)C(O)-lower alkylene-OR⁰, or —N(R⁰)S(O)₂— loweralkyl, and even more preferably —OR^(o), —N(R^(o))C(O)R^(o), or—N(R^(o))S(O)₂-lower alkyl.

Group G²: halogen, lower alkyl, halogeno-lower alkyl, loweralkylene-OR⁰, —OR⁰, —O-halogeno-lower alkyl, —N(R⁰)₂, —N(R⁰)-loweralkylene-OR⁰, —N(R⁰)-lower alkylene-CO₂R^(o), —N(R⁰)C(O)R^(o),—N(R⁰)C(O)OR⁰, —N(R⁰)C(O)-aryl, —N(R⁰)C(O)-lower alkylene-OR⁰,—N(R⁰)C(O)-lower alkylene-N(R⁰)₂, —N(R⁰)C(O)N(R⁰)₂, —N(R⁰)C(═NR⁰)-loweralkyl, —N(R⁰)S(O)₂-lower alkyl, —N(lower alkylene-OR⁰)—S(O)₂-loweralkyl, —N(lower alkylene-CO₂R⁰)—S(O)₂-lower alkyl, —N(R⁰)S(O)₂-loweralkylene-CO₂R⁰, —N(R⁰)S(O)₂-lower alkylene-S(O)₂-lower alkyl,—N(R⁰)S(O)₂-aryl, —N(R⁰)S(O)₂N(R⁰)₂, —S(O)₂-lower alkyl, —CO₂R^(o),—CO₂-lower alkylene-Si(lower alkyl)₃, —C(O)N(R⁰)₂, —C(O)N(R⁰)-loweralkylene-OR^(o), —C(O)N(R⁰)-lower alkylene-N(R⁰)₂, —C(O)N(R⁰)-loweralkylene-CO₂R⁰, —C(O)N(R⁰)—O-lower alkylene-heterocyclic group,heterocyclic group, —C(O)R⁰, —C(O)-lower alkylene-OR⁰, —C(O)-loweralkylene-N(R⁰)₂, —C(O)-heterocyclic group, and oxo.

Provided that the “aryl” and the “heterocyclic group” in Group G² may beeach substituted with a group selected from the group consisting ofhalogen, lower alkyl, halogeno-lower alkyl, —OR⁰, —O-halogeno-loweralkyl, and oxo.

The substituent for the “aryl” which may be substituted in R¹ ispreferably a group selected from Group G³, and more preferably —OR⁰ orlower alkylene-OR⁰.

Group G³: halogen, lower alkyl, halogeno-lower alkyl, —OR⁰,—O-halogeno-lower alkyl, lower alkylene-OR⁰, and —CO₂R⁰.

The substituent for the “aryl” and the “heterocyclic group” which may besubstituted in R² is preferably a group selected from Group G⁴, morepreferably halogen, lower alkyl, or —OR⁰, and even more preferablyhalogen.

Group G⁴: halogen, —CN, nitro, lower alkyl, halogeno-lower alkyl, —OR⁰,—N(R⁰)₂, —CO₂R, —C(O)N(R⁰)₂, —OS(O)₂-lower alkyl, and oxo.

The substituent for the “lower alkylene” which may be substituted in R⁷is preferably a group selected from Group G⁵, more preferably halogen.

Group G⁵: halogen, —OR⁰, —N(R⁰)₂, and aryl.

Provided that the “aryl” in Group G⁵ may be substituted with a groupselected from the group consisting of halogen, lower alkyl,halogeno-lower alkyl, —OR⁰, and —O-halogeno-lower alkyl.

The substituent for the “aryl” and the “heterocyclic group” which mayeach be substituted in R⁷ is preferably a group selected from Group G⁶,and more preferably halogen, —OR⁰, lower alkylene-OR⁰, —CO₂R⁰, loweralkylene-CO₂R⁰, —O-lower alkylene-CO₂R⁰, or oxo.

Group G⁶: halogen, lower alkyl which may be substituted with —OR⁰,halogeno-lower alkyl which may be substituted with —OR⁰, —OR⁰, —CN,—N(R⁰)₂, —CO₂R⁰, —CO₂-lower alkylene-aryl, —C(O)N(R⁰)₂, loweralkylene-OC(O)R⁰, lower alkylene-OC(O)aryl, lower alkylene-CO₂R⁰,halogeno-lower alkylene-CO₂R⁰, lower alkylene-CO₂-lower alkylene-aryl,lower alkylene-C(O)N(R⁰)₂, halogeno-lower alkylene-C(O)N(R⁰)₂, —O-loweralkylene-CO₂R⁰, —O-lower alkylene-CO₂-lower alkylene-aryl, —O-loweralkylene-C(O)N(R⁰)₂, —O-halogeno-lower alkylene-CO₂R⁰, —O-halogeno-loweralkylene-C(O)N(R)₂, —C(O)N(R⁰)S(O)₂-lower alkyl, loweralkylene-C(O)N(R⁰)S(O)₂-lower alkyl, —S(O)₂-lower alkyl, —S(O)₂N(R⁰)₂,heterocyclic group, —C(═NH)NH₂, —C(—NH)═NO—C(O)O—C₁₋₁₀ alkyl,—C(═NOH)NH₂, —C(O)N═C(N(R⁰)₂)₂, —N(R⁰)C(O)R⁰, —N(R⁰)C(O)-loweralkylene-OR⁰, —N(R⁰)C(O)OR⁰, —N(R⁰)S(O)₂-lower alkyl, —C(aryl)₃, andoxo.

Provided that the “aryl” and the “heterocyclic group” in Group G⁶ mayeach be substituted with a group selected from the group consisting ofhalogen, lower alkyl, halogeno-lower alkyl, —OR⁰, —O-halogeno-loweralkyl, oxo, and thioxo (═S).

The substituent for the “aryl” which may be substituted in R⁴; and thesubstituent for the “heteroaryl” which may be substituted in R⁷ arepreferably a group selected from the group consisting of halogen, loweralkyl, halogeno-lower alkyl, —OR⁰, and —O-halogeno-lower alkyl.

The substituent for the “aryl” and “heteroaryl” which may be eachsubstituted in R⁹ is preferably a group selected from the groupconsisting of halogen, lower alkyl, halogeno-lower alkyl, —OR⁰, and—O-halogeno-lower alkyl.

The substituent for the “aryl” which may each be substituted in R⁵ ispreferably a group selected from the group consisting of halogen, loweralkyl, halogeno-lower alkyl, —OR⁰, and —O-halogeno-lower alkyl.

Preferred embodiments of the present invention will be described below.

(a) R¹ is preferably -(lower alkylene which may be substituted)-OH, orcycloalkyl, aryl, or a heterocyclic group, which may each besubstituted. More preferably, it is (lower alkylene which may besubstituted)-OH, or cyclopentyl, cyclohexyl, phenyl, tetrahydrofuryl,tetrahydropyranyl, pyrrolidyl, or piperidyl, which may be eachsubstituted. More preferably, it is (lower alkylene which may besubstituted with a group selected from the group consisting of phenylwhich may be substituted with halogen, lower alkyl, or —OR⁰, and—OH)—OH, or cycloalkyl substituted with a group selected from the groupconsisting of —OR^(o), —N(R^(o))₂, —N(R^(o))C(O)R^(o),—N(R^(o))C(O)-lower alkylene-OR^(o), —N(R^(o))S(O)₂-lower alkyl, and aheterocyclic group. Even more preferably, it is (lower alkylene whichmay be substituted with a group selected from the group consisting ofphenyl which may be substituted with halogen, lower alkyl or —OR⁰, and—OH)—OH, or cyclopentyl or cyclohexyl, which is each substituted with agroup selected from the group consisting of —OR^(o), —N(R^(o))₂,—N(R^(o))C(O)R^(o), —N(R^(o))C(O)-lower alkylene-OR^(o),—N(R^(o))S(O)₂-lower alkyl and a heterocyclic group. Particularlypreferably, it is cyclohexyl substituted with a group selected from thegroup consisting of —OR^(o), —N(R^(o))C(O)R^(o), and—N(R^(o))S(O)₂-lower alkyl.

(b) R² is preferably aryl which may be substituted, and more preferablyphenyl which may be substituted with halogen, lower alkyl, or —OR⁰, andeven more preferably phenyl substituted with halogen.

(c) R³ is preferably —H.

(d) R⁴ is preferably —N(R⁰)-lower alkylene-(aryl or heteroaryl, whichmay be each substituted) or —N(R⁰)—O-lower alkylene-(aryl or heteroaryl,which may be each substituted). More preferably, it is —NH-loweralkylene-(phenyl, pyridyl, N-oxidopyridyl, thienyl, or thiazolyl, whichmay each be substituted) or —NH—O-lower alkylene-(phenyl, pyridyl,N-oxidopyridyl, thienyl, or thiazolyl, which may be each substituted).More preferably, it is —NH-lower alkylene-(phenyl, pyridyl,N-oxidopyridyl, thienyl, or thiazolyl, which may each be substitutedwith a group selected from the group consisting of halogen, —OR⁰, loweralkylene-OR⁰, —CO₂R⁰, lower alkylene-CO₂R⁰, and —O-lower alkylene-CO₂R⁰or —NH—O-lower alkylene-(phenyl, pyridyl, N-oxidopyridyl, thienyl, orthiazolyl, which may each be substituted with a group selected from thegroup consisting of halogen, —OR⁰, lower alkylene-OR⁰, —CO₂R⁰, loweralkylene-CO₂R⁰, and —O-lower alkylene-CO₂R⁰). Even more preferably, itis —NH-lower alkylene-(phenyl which may be substituted with a groupselected from the group consisting of halogen, —OR⁰, lower alkylene-OR⁰,—CO₂R⁰, lower alkylene-CO₂R⁰, and —O-lower alkylene-CO₂R⁰) or—NH—O-lower alkylene-(phenyl which may be substituted with a groupselected from the group consisting of halogen, —OR⁰, lower alkylene-OR⁰,—CO₂R⁰, lower alkylene-CO₂R⁰, and —O-lower alkylene-CO₂R⁰.

(e) R⁵ is preferably halogen or —OR⁰.

(f) m is preferably 0 or 1, and more preferably 0.

In further preferred embodiments, the compounds having any combinationof each of the preferable groups as described in (a) to (f) above arepreferred.

Furthermore, other preferred embodiments for the compound of the presentinvention represented by the general formula (I) are shown below.

(1) A compound represented by the general formula (I), wherein R³ is —H.

(2) The compound as described in (1), wherein R² is phenyl which may besubstituted with halogen, lower alkyl, or —OR⁰.

(3) The compound as described in (2), wherein R⁴ is —N(R⁰)-loweralkylene-(aryl or heteroaryl, which may each be substituted), or—N(R⁰)—O-lower alkylene-(aryl or heteroaryl, which may each besubstituted).

(4) The compound as described in (3), wherein R¹ is (lower alkylenewhich may be substituted with a group selected from the group consistingof phenyl which may be substituted with halogen, lower alkyl or —OR⁰,and —OH)—OH; or cycloalkyl substituted with a group selected from thegroup consisting of —OR⁰, —N(R⁰)₂, —N(R⁰)C(O)R⁰, —N(R⁰)-loweralkylene-OR⁰, —N(R⁰)S(O)₂-lower alkyl, and a heterocyclic group.

(5) A compound represented by the general formula (I) selected from thegroup consisting of:

-   (3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,-   (3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-N-[(1-oxidopyridin-2-yl)methoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,-   3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic    acid,-   (4-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenyl)acetic    acid,-   (3-{[({[(3R,4R)-3-(2,4-dichlorophenyl-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic    acid,-   {3-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]phenyl}(difluoro)acetic    acid,-   (3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-N-(2-{3-[(methylsulfonyl)carbamoyl]phenyl}ethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,-   {4-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]phenyl}acetic    acid, and-   4-(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)butanoic    acid;    or a pharmaceutically acceptable salt thereof

Furthermore, in the present specification, the “irritable bowelsyndrome” (which is hereinafter referred to as IBS) includes diarrheatype IBS, constipation type IBS, and alternating type IBS. The diseaseto which the therapeutic agent of the present invention is applied ispreferably diarrhea type IBS or alternating type IBS, and particularlypreferably diarrhea type IBS.

The compounds of the present invention may exist in the form of othertautomers or geometrical isomers depending on the kind of thesubstituents. In the present specification, the compound may bedescribed in only one form of an isomer, but the present inventionincludes the isomers, an isolated form or a mixture of the isomers.

Furthermore, the compound (I) may have asymmetric carbons or axialasymmetries, and correspondingly, it may exist in the form of opticalisomers such as an (R)-form, an (S)-form, and the like. The compound ofthe present invention includes both a mixture and an isolated form ofthese optical isomers.

In addition, a pharmaceutically acceptable prodrug of the compound (I)is also included in the present invention. The pharmaceuticallyacceptable prodrug refers to a compound, having a group which can beconverted into an amino group, OH, CO₂H, and the like of the presentinvention, by solvolysis or under a physiological condition. Examples ofthe group which forms the prodrug include those as described in Prog.Med., 5, 2157-2161 (1985), or “Pharmaceutical Research and Development”(Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198.

Furthermore, the compound of the present invention may form anacid-addition salt or a salt with a base, depending on the kind of thesubstituents, and these salts are included in the present invention aslong as they are pharmaceutically acceptable salts. Specifically,examples thereof include acid addition salts with inorganic acids suchas hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid, and the like, and with organic acids suchas formic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, aspartic acid, glutamic acid, or the like, andsalts with inorganic bases such as sodium, potassium, magnesium,calcium, aluminum, and the like, and with organic bases such asmethylamine, ethylamine, ethanolamine, lysine, ornithine, and the like,ammonium salts.

In addition, the present invention also includes various hydrates andsolvates, and polymorphism of the compound of the present invention anda pharmaceutically acceptable salt thereof. Furthermore, the presentinvention also includes the compounds that are labeled with variousradioactive or non-radioactive isotopes.

(Production Process)

The compound of the present invention and a pharmaceutically acceptablesalt thereof may be prepared by applying various known syntheticmethods, by the use of the characteristics based on their basicbackbones or the kind of the substituents. Here, depending on the kindof the functional groups, it is in some cases effective from theviewpoint of the preparation techniques to substitute the functionalgroup with an appropriate protecting group (a group which may be easilyconverted into the functional group), during the steps from startingmaterials to intermediates. Examples of such functional groups includean amino group, a hydroxyl group, a carboxyl group, and the like, andexamples of a protecting group thereof include those as described in“Protective Groups in Organic Synthesis” (3^(rd) edition, 1999), editedby Greene and Wuts, which may be optionally selected and used inresponse to the reaction conditions. By such a method, a desiredcompound can be obtained by introducing the protecting group andcarrying out the reaction, and then, if desired, removing the protectinggroup.

In addition, a prodrug of the compound (I) can be prepared byintroducing a specific group during the steps from starting materials tointermediates, in the same manner as for the aforementioned protectinggroups, or by carrying out the reaction using the obtained compound (I).The reaction may be carried out by employing a method known to a personskilled in the art, such as general esterification, amidation, anddehydration.

Hereinbelow, the representative production processes of the compounds ofthe present invention will be described. Each of the productionprocesses can also be carried out with reference to the referencedocuments attached to the present description. Further, the productionprocesses of the present invention are not limited to the examples asshown below.

(Production Process 1)

This production process is a process for obtaining the compound (I) ofthe present invention by subjecting a carboxylic acid compound (1) andan amine compound (2) to amidation.

The reaction can be carried out using equivalent amounts of thecarboxylic acid compound (1) and the amine compound (2), or an excessamount of either, and stirring them from under cooling to under heating,preferably at −20° C. to 60° C., usually for 0.1 hour to 5 days, in asolvent which is inert to the reaction, in the presence of a condensingagent. The solvent as used herein is not particularly limited, butexamples thereof include aromatic hydrocarbons such as benzene, toluene,xylene, and the like, halogenated hydrocarbons, such as dichloromethane,1,2-dichloroethane, chloroform, and the like, ethers such as diethylether, tetrahydrofuran (THF), dioxane, dimethoxyethane, and the like,N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),N-methylpyrrolidin-2-one (NMP), dimethyl sulfoxide (DMSO), ethylacetate, acetonitrile, water, and the like, or mixture thereof Examplesof the condensing agent include1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC),dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), diphenylphosphoryl azide, phosphorous oxychloride, and the like, but are notlimited to these. An additive (for example, 1-hydroxybenzotriazole(HOBt), and the like) may be preferable for the reaction in some cases.It may be advantageous for the smooth progress of the reaction to carryout the reaction in the presence of an organic base such astriethylamine, N,N-diisopropylethylamine, pyridine,N,N-dimethyl-4-aminopyridine (DMAP), and the like, or an inorganic basesuch as potassium carbonate, sodium carbonate, potassium hydroxide, andthe like in some cases.

In addition, a process in which the carboxylic acid compound (1) isderived into a reactive derivative, and then reacted with the aminecompound (2) can also be used. Examples of the reactive derivative ofthe carboxylic acid as used herein include an acid halide obtained bythe reaction with a halogenating agent such as phosphorous oxychloride,thionyl chloride, and the like, a mixed acid anhydride obtained by thereaction with isobutyl chloroformate, or the like, an active esterobtained by the condensation with 1-hydroxybenzotriazole or the like,and others. The reaction of the reactive derivative and the aminecompound (2) can be carried out from under cooling to under heating,preferably at −20° C. to 60° C., in a solvent which is inert to thereaction, such as halogenated hydrocarbons, aromatic hydrocarbons,ethers, and the like.

Production Process 2: Other Production Processes

Furthermore, some compounds represented by the formula (I) can also beprepared by subjecting the compound of the present invention obtained asabove to any combination of the processes that are usually employed by askilled person in the art, such as conventional amidation, hydrolysis,N-oxidation, reductive amination, sulfonylation, oxidation, reduction,N-alkylation, O-alkylation, and the like. For example, they can beprepared by the reactions as below, the methods described in Examples tobe described later, a method apparent to a skilled person in the art, ora modified method thereof

2-1: Amidation

An amide compound can be obtained by subjecting a carboxylic acidcompound and an amine compound to amidation.

The amidation can be carried out in the same manner as in ProductionProcess 1.

2-2: Hydrolysis

A compound having a carboxyl group can be prepared by hydrolyzing acompound having an ester group.

The reaction can be carried out from under cooling to under heating in asolvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons,alcohols, DMF, DMA, NMP, DMSO, pyridine, water, and the like in thepresence of an acid including mineral acids such as sulfuric acid,hydrochloric acid, hydrobromic acid, and the like, and organic acidssuch as formic acid, acetic acid, and the like; or in the presence of abase such as lithium hydroxide, sodium hydroxide, potassium hydroxide,potassium carbonate, sodium carbonate, cesium carbonate, ammonia, andthe like.

2-3: N-oxidation

An N-oxide compound can be prepared by oxidating the nitrogen atom of aheterocycle having a nitrogen atom, such as pyridine and the like, withvarious oxidants.

The reaction can be carried out from under cooling, at room temperatureto under heating, using an equivalent amount or excess amount ofm-chloroperbenzoic acid, peracetic acid, aqueous hydrogen peroxide, andthe like as an oxidant, in a solvent such as halogenated hydrocarbons,acetic acid, water, and the like.

2-4: Reductive Amination

An amine compound can be alkylated by reducing an imine compound whichis prepared from a primary or secondary amine compound and a carbonylcompound.

The reaction can be carried out using equivalent amounts of an aminecompound and a carbonyl compound, or an excessive amount of eitherthereof, in the presence of a reducing agent, in a solvent such ashalogenated hydrocarbons, alcohols, ethers, and the like. As thereducing agent, sodium cyanoborohydride, sodium triacetoxyborohydride,sodium borohydride, and the like can be used. The reaction may bepreferably carried out in the presence of an acid such as acetic acid,hydrochloric acid, titanium (IV) isopropoxide complexes, and the like insome cases.

2-5: Sulfonylation

A sulfonamide compound can be obtained by the sulfonylation of an aminecompound.

The reaction can be carried out, for example, from under cooling, atroom temperature to under heating, by using equivalent amounts of anamine compound and a sulfonyl halide, or an excessive amount of eitherthereof, in a solvent such as aromatic hydrocarbons, ethers, halogenatedhydrocarbons, pyridine, and the like. It may be advantageous for thesmooth progress of the reaction to carry out the reaction in thepresence of an organic base such as triethylamine,N,N-diisopropylethylamine, pyridine, and the like, or an inorganic basesuch as potassium carbonate, sodium carbonate, potassium hydroxide, andthe like in some cases.

(Production Processes for Starting Compounds)

The starting material used for the preparation of the compound of thepresent invention can be prepared, for example, by applying the methodsdescribed below, the methods described in Production Examples to bedescribed later, a known method, a method apparent to a skilled personin the art, or a modified method thereof

(Starting Material Synthesis 1)

Step 1:

A compound (5) can be obtained by reacting a compound (3) with acompound (4).

The reaction can be carried out from at room temperature to underheating, using equivalent amounts of the compound (3) and the compound(4) or an excessive amount of either thereof, in a solvent such asethers, halogenated hydrocarbons, aromatic hydrocarbons, and the like.

Step 2:

When R³ is —H, a compound (6) in which the substituents at the 3- and4-positions are trans can be obtained by isomerizing the compound (5).

The reaction can be carried out by treating the compound (5) with a basesuch as sodium hydroxide, potassium hydroxide, and the like, from atroom temperature to under heating, in a solvent such as halogenatedhydrocarbons, alcohols, water, and the like.

(Starting Material Synthesis 2)

The compound (3) can be obtained by carrying outdehydration-condensation of a compound (7) with a compound (8).

The reaction can be carried out from at room temperature to underheating, using equivalent amounts of the compound (7) and the compound(8) or an excessive amount of either thereof, in a solvent such ashalogenated hydrocarbons, aromatic hydrocarbons, and the like. It may beadvantageous for the smooth progress of the reaction to use adehydrating agent such as anhydrous sodium sulfate, anhydrous magnesiumsulfate, Molecular Sieves, and the like in some cases.

(Starting Material Synthesis 3)

Step 1:

A compound (10) can be obtained by reacting a compound (9) with anitrite.

The reaction can be carried out from under cooling, at room temperatureto under heating in a solvent such as ethers, halogenated hydrocarbons,alcohols, and the like in the presence of a nitrite such as ethylnitrite, butyl nitrite, isoamyl nitrite, and the like. According to thecompounds, it is advantageous for the progress of the reaction to carryout the reaction in the presence of an acid such as acetic acid,hydrochloric acid, and the like, or a base such as sodium methoxide,sodium ethoxide, potassium tert-butoxide, and the like in some cases.

Step 2

A compound (11) can be prepared by subjecting the compound (10) torearrangement and then to hydrolysis.

The rearrangement reaction can be carried out by treating the compound(10) with thionyl chloride, or the like under cooling.

The hydrolysis reaction can be carried out from at room temperature tounder heating, in a solvent such as alcohols, water, and the like, usinga base such as sodium hydroxide, potassium hydroxide, and the like.

Step 3

The compound (4) can be obtained by the dehydration of the compound(11).

The dehydration reaction can be carried out from at room temperature tounder heating, using acetyl chloride or the like as a dehydrating agent.

The compound of the present invention is isolated and purified as a freecompound, a pharmaceutically acceptable salt, hydrate, solvate, orpolymorphism thereof. The pharmaceutically acceptable salt of thecompound (I) of the present invention can be prepared by a saltformation reaction within a conventional technology.

The isolation and purification can be carried out by employing generalchemical operations such as extraction, fractional crystallization,various types of fractional chromatography, and the like.

Various isomers can be separated by selecting an appropriate startingcompound, or by making use of the difference in the physicochemicalproperties between isomers. For example, the optical isomer can bederived into a stereochemically pure isomer by means of general opticalresolution methods (for example, fractional crystallization for inducingto diastereomeric salts with optically active bases or acids,chromatography using a chiral column, etc., and the like). In addition,the isomers can also be prepared from an appropriate optically activestarting compound.

The pharmacological activity of the compound of the present inventionwas confirmed by the following test.

Test Example 1 BB2 Receptor Antagonistic Activity

A BB2 receptor binding test was carried out using a membrane sampleprepared from a human prostate cancer-derived PC-3 cell. The PC-3 cellwas cultured using an RPMI-1640 medium containing 5% fetal bovine serum,and then a membrane sample was prepared by the following methods. Thecells detached by a trypsin treatment were added with a 50 mM Tris-HClbuffer (pH 7.4, containing 0.2 mg/ml trypsin inhibitor and 0.2 mg/mlbenzamidine), and homogenized by Polytron. The cell suspension wascentrifuged at 1,500 rpm for 10 minutes, and the supernatant thusobtained was subjected to 1 hour of ultracentrifugation at 37,000×g. Theprecipitate was suspended in the aforementioned buffer to aconcentration of 0.4 mg protein/ml, and stored at −80° C.

The BB2 receptor binding test was carried out by the following method,and the receptor antagonistic activity of a compound to be tested wascalculated. A 50 μl of the membrane sample, 50 μl of an assay buffer (20mM HEPES-HBSS containing 0.1% bovine serum albumin and 0.1 mg/mlbacitracin, pH 7.4), ¹²⁵I [Tyr⁴] bombesin (0.075 nM) and 2 μl of thecompound to be tested dissolved in dimethyl sulfoxide were added to a 96well assay plate, and incubated at room temperature for 2 hours.Non-specific binding was measured using 1 μM of bombesin. Aftercompletion of the incubation, the reaction solution was filtered througha Whatman GF/B filter which had been soaked in 0.5% polyethyleneimine.The radioactivity on the filter was measured using a microplatescintillation counter (Top Count, Perkin-Elmer Co., Ltd.). The 50%binding inhibition concentrations of the representative ExampleCompounds are shown in Table 12. Further, Ex represents the number ofthe Example compound.

TABLE 12 Ex IC₅₀ (nM) 61 12.8 62 18.3 236 3.0 542 4.7 560 4.8 589 5.7631 4.5 700 6.7 701 7.4 709 8.9 712 6.7 856 6.8

Test Example 2 Restraint Stress-Induced Defecation Model

The compound to be tested of the present test was used by dissolving inwater for injection containing 20% propylene glycol+20% Tween 80 or a0.5% MC (methyl cellulose) solution.

Fifteen minutes after oral administration of the compound to be testedto a fed male Wistar rat, the animal was put into a restraint stresscage (KN-468, Natsume Seisakusho Co Ltd.). The number of feces excretedduring a period from the restriction commencement to 1 hour thereafterwas measured. Normal group was put into a separate cage, and number offeces excreted during 1 hour was measured in the same manner.

The inhibitory rates (%) of the representative Example Compounds whenthey were orally administered at a dose of 1 mg/kg are shown in Table13. As a result, it was confirmed that the compound of the presentinvention exhibited an excellent action to improve the bowel movementsymptom.

TABLE 13 Ex Inhibitory Rate (%) 542 40.0 560 62.1 589 73.9 631 53.8 70069.8 701 41.3 709 41.5 712 55.0 856 61.4

As a result of the test as described above, it was confirmed that thecompound of the present invention has a BB2 receptor inhibitory action.From this point, it is obvious that the compound is useful as atherapeutic agent for the diseases associated with the BB2 receptors, inparticular, IBS, cancers, functional dyspepsia, diabetic gastroparesis,reflux esophagitis, peptic ulcer, and the like.

The preparation containing one or two or more of the compound (I) of thepresent invention or a salt thereof as an active ingredient can beprepared in accordance with a generally used method, using apharmaceutical carrier, an excipient, and the like, which are generallyemployed in the art.

The administration can be accompanied by any mode of oral administrationvia tablets, pills, capsules, granules, powders, liquid preparations, orthe like; or parenteral administration via injections such asintraarticular, intravenous, or intramuscular injections, suppositories,eye drops, eye ointments, transdermal liquid preparations, ointments,transdermal patches, transmucosal liquid preparations, transmucosalpatches, inhalations, and the like.

Regarding the solid composition for oral administration according to thepresent invention, tablets, powders, granules, or the like are used. Insuch a solid composition, one or two or more of active ingredients aremixed with at least one inactive excipient such as lactose, mannitol,glucose, hydroxypropylcellulose, microcrystalline cellulose, starch,polyvinyl pyrrolidone, and/or magnesium aluminometasilicate, and thelike. According to a conventional method, the composition may containinert additives such as a lubricant such as magnesium stearate, adisintegrator such as carboxymethyl starch sodium, a stabilizing agent,and a solubilizing agent. As necessary, tablets or pills may be coatedwith a sugar coating, or a film of a gastric or enteric material.

The liquid composition for oral administration includes pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs, or thelike, and contains a generally used inert diluent such as purified waterand ethanol. In addition to the inert solvent, this liquid compositionmay contain an auxiliary agent such as a solubilizing agent, amoistening agent, and a suspending agent, a sweetener, a flavor, anaroma, and an antiseptic.

The injections for parenteral administration include sterile aqueous ornon-aqueous liquid preparations, suspensions, and emulsions. As theaqueous solvent, for example, distilled water for injection andphysiological saline are included. Examples of the non-aqueous solventinclude propylene glycol, polyethylene glycol, plant oils such as oliveoil, alcohols such as ethanol, and Polysorbate 80 (JapanesePharmacopeia), and the like. Such a composition may further contain atonicity agent, an antiseptic, a moistening agent, an emulsions, adispersant, a stabilizer, or a solubilizing agent. These are sterilized,for example, by filtration through a bacteria retaining filter, blendingof a bactericide, or irradiation. In addition, these can also be used bypreparing a sterile solid composition, and dissolving or suspending insterile water or a sterile solvent for injection prior to its use.

The drug for external use includes ointments, plasters, creams, jellies,cataplasms, sprays, lotions, eye drops, eye ointments, and the like. Thedrug contains generally used ointment bases, lotion bases, aqueous ornon-aqueous solutions, suspensions, emulsions, and the like. Examples ofthe ointment or lotion bases include polyethylene glycol, propyleneglycol, white vaseline, bleached beeswax, polyoxyethylene hydrogenatedcastor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol,lauromacrogol, sorbitan sesquioleate, and the like.

Regarding a transmucosal agent such as an inhalation, a transnasalagent, and the like, those in a solid, liquid, or semi-solid state areused, and may be produced in accordance with a conventionally knownmethod. For example, a known excipient, and in addition, a pH adjustingagent, an antiseptic, a surfactant, a lubricant, a stabilizing agent, athickening agent, and the like may be added thereto, if desired. Fortheir administration, an appropriate device for inhalation or blowingmay be used. For example, a compound may be administered alone or as apowder of formulated mixture, or as a solution or suspension incombination with a pharmaceutically acceptable carrier, using aconventionally known device or sprayer, such as a measuredadministration inhalation device and the like. The dry powder inhaler orthe like may be for single or multiple administration use, and a drypowder or a powder-containing capsule may be used. Alternatively, thismay be in a form such as a high pressurized aerosol spray which uses anappropriate propellant, for example, a suitable gas such aschlorofluoroalkane, hydrofluoroalkane, carbon dioxide, and the like.

In the case of conventional oral administration, the daily dose may begenerally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30mg/kg, and even more preferably 0.1 to 10 mg/kg, per body weight, andthis is administered in one portion or in 2 to 4 divided portions. Also,in the case of intravenous administration, the daily dose is from about0.0001 to 10 mg/kg per body weight, once a day or twice or more times aday. In addition, a transmucosal agent is administered at a dose fromabout 0.001 to 100 mg/kg per body weight, once a day or twice or moretimes a day. The dose is appropriately decided in response to anindividual case by taking symptoms, age, gender, or the like intoconsideration.

The compound of the present invention can be used in combination withvarious therapeutic or prophylactic agents for the diseases, for whichthe compound of the present invention is considered effective. Thecombined preparation may be administered simultaneously, or separatelyand continuously or at a desired time interval. The preparations to beco-administered may be a blend, or prepared individually.

EXAMPLES

Hereinbelow, the production processes for the compound (I) of thepresent invention will be described in more detail with reference toExamples. The compound of the present invention is not limited to thecompounds described in Examples below. Further, the production processesfor the starting compounds will be described in Production Examples.

In addition, the following abbreviations are used in Examples,Production Examples, and Tables to be described later.

PEx: Production Example, Ex: Example, No: Compound No., Data:Physicochemical Data (EI+: m/z value in ELMS (cation) (unless otherwisementioned, (M)⁺.), FAB+: m/z value in FAB-MS (cation) (unless otherwisementioned, (M+H)⁺.), FAB−: m/z value in FAB-MS (anion) (unless otherwisementioned, (M−H)⁻.), ESI+: m/z value in ESI-MS (cation) (unlessotherwise mentioned, (M+H)⁺.), ESI−: m/z value in ESI-MS (anion) (unlessotherwise mentioned, (M−H)⁻.), CI+: m/z value in CI-MS (cation) (unlessotherwise mentioned, (M+H)⁺.), APCI+: m/z value in APCI-MS (cation)(unless otherwise mentioned, (M+H)⁺.), APCI−: m/z value in APCI-MS(anion) (unless otherwise mentioned, (M−H)⁻.), NMR1: δ (ppm) ofcharacteristic peak in δ (ppm) by ¹H-NMR in DMSO-d₆), Structure:Structural Formula (a case where HCl, HBr, fum, or TFA is described inthe structural formula indicates that the compound is hydrochloride,hydrobromide, fumarate, or trifluoroacetate, respectively. In the casewhere a numeral is attached before a salt component, the numeral means amolar ratio of the compound to the salt component. For example, a casewhere 2HCl is described means that the compound is dihydrochloride.Further, a case where H₂O is described in the structural formulaindicates that the compound is a hydrate in each case.), Syn: ProductionProcess (the numeral shows that it was prepared using a correspondingstarting material, similar to the case of an Example Compound having itsnumber as the Example No.). In the case where P is attached before thenumeral, the number shows that it was produced using a correspondingstarting material, similar to the case of a Production Example Compoundhaving its number as the Prosuction Example No. A case where a pluralityof the numerals is described indicates that the compound was prepared bycarrying out the reaction in order starting from the front numeral,using a corresponding starting material. Note: (the racemic mixturemeans a racemic mixture, the diastereo mixture means a diastero mixture,and the chiral compound means a chiral compound, in which a part of itsstereochemistry is not clear. Further, less polar and more polar mean alow polarity product and a high polarity product, respectively, ascompared with the corresponding diastereomers, in thin layerchromatography. Further, 3,4-trans, 1′,2′-cis, and the like mean therelative configurations of the substituents or the like. Provided thatthe numeral which is not dashed means the position substituted in thetetrahydroisoquinolin-1-one ring, and the dashed numeral means theposition substituted in the substituent at the 2-position in atetrahydroisoquinolin-1-one ring. For example, 3,4-trans indicates thatthe substituents at the 3- and 4-positions in thetetrahydroisoquinolin-1-one ring are trans.) Boc: a tert-butoxycarbonylgroup, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

In addition,

indicates that the double bond is cis or trans, or a mixture thereof

Production Example 1

10 g of 5-(benzyloxy)-1H-indene-1,2(3H)-dione 2-oxime was added to 20 mlof thionyl chloride at 0° C., followed by stirring for 20 minutes underthe same condition. After warming to room temperature, thionyl chloridewas evaporated under reduced pressure. To the residue was added 20 ml ofa 40% aqueous potassium hydroxide solution, followed by heating underreflux overnight. After cooling to room temperature, and neutralizing bythe addition of concentrated hydrochloric acid, the precipitated solidwas collected by filtration to obtain 9.9 g of4-(benzyloxy)-2-(carboxymethyl)benzoic acid as a dark brown powder.

Production Example 2

To a mixture of 2.01 g of diethyl[3-(1,3-dioxolan-2-yl)phenyl]malonate,2.89 g of calcium chloride, and 50 ml of ethanol was added 2.47 g ofsodium borohydride under ice-cooling, followed by stirring at the sametemperature for 2 hours and at room temperature for 4 hours. To thereaction solution was added 10 ml of water at room temperature, followedby stirring for 30 minutes. The insoluble material was separated byfiltration using Celite, and the filtrate was concentrated under reducedpressure to obtain 0.76 g of2-[3-(1,3-dioxolan-2-yl)phenyl]propane-1,3-diol as a colorless oilysubstance.

Production Example 3

A mixture of 1.83 g of 2-[3-(1,3-dioxolan-2-yl)phenyl]propane-1,3-diyldiacetate and 60 ml of a 83% aqueous acetic acid solution was stirred at50° C. for 2 hours. The reaction solution was concentrated under reducedpressure to obtain 1.59 g of 2-(3-formylphenyl)propane-1,3-diyldiacetate as a colorless oily substance.

Production Example 4

To a solution of 958 mg of (6-methylpyridin-3-yl)methanol, 1.3 ml oftriethylamine, and 95 mg of DMAP in 40 ml of dichloromethane was addeddropwise 1.08 ml of benzoyl chloride, followed by stirring at roomtemperature. To the reaction solution was added water, followed bycarrying out an extraction operation with chloroform. The organic layerwas washed with a saturated aqueous sodium chloride solution, then driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate) to obtain 1767 mg of(6-methylpyridin-3-yl)methyl benzoate.

Production Example 5

To a solution of 1767 mg of (6-methylpyridin-3-yl)methyl benzoate in26.5 ml of chloroform was added 2440 mg of m-chloroperbenzoic acid underice-cooling, followed by stirring for 1 hour. An aqueous potassiumcarbonate solution was added thereto to carry out a liquid separationoperation, and the organic layer was washed with a saturated aqueoussodium chloride solution and then dried over anhydrous magnesiumsulfate. The residue was concentrated under reduced pressure to obtain1891 mg of (6-methyl-1-oxidopyridin-3-yl)methyl benzoate.

Production Example 6

To a solution of 1891 mg of (6-methyl-1-oxidopyridin-3-yl)methylbenzoate in 38 ml of DMF was added 11 ml of trifluoroacetic anhydride,followed by stirring at room temperature overnight. After evaporatingtrifluoroacetic anhydride under reduced pressure, a saturated aqueoussodium hydrogen carbonate solution was added thereto, followed byextraction with chloroform. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 3.675 g of[6-(hydroxymethyl)pyridin-3-yl]methyl benzoate.

Production Example 7

To a solution of 858 mg of pyrazine-2,5-diyl bis(methylene) diacetate in8.6 ml of methanol was added 600 mg of zeolite, followed by heatingunder reflux for 4 days. Zeolite was removed by filtration and thenconcentrated, and the residue was purified by silica gel columnchromatography (eluent: chloroform-methanol) to obtain 209 mg of[5-(hydroxymethyl)pyrazine-2-yl]methyl acetate.

Production Example 8

To a mixture of 313 mg of 6-(hydroxymethyl)nicotinamide, 540 mg oftriphenylphosphine, 503 mg of N-hydroxyphthalimide, and 4.7 ml of THFwas added dropwise 0.53 ml of diisopropyl azodicarboxylate, followed bystirring overnight. After concentration, the solid thus produced wassuspended in water, and ethyl acetate was added thereto. After stirringfor 30 minutes, the solid was collected by filtration to obtain 292 mgof 6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}nicotinamide.

Production Example 9

To a suspension of 292 mg of6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}nicotinamide in4.4 ml of methanol was added 0.2 ml of a 40% methyl amine/methanolsolution, followed by stirring at room temperature for 1 hour. Thereaction solution was concentrated, ethyl acetate was added thereto, andthe precipitated crystal was separated by filtration and thenconcentrated under reduced pressure to obtain 146 mg of6-[(aminooxy)methyl]nicotinamide.

Production Example 10

To a mixture of 3.0 g of 6-chloronicotinic acid and 111 ml of THF wasadded 6.4 g of potassium tert-butoxide, followed by heating under refluxfor 1 day. The reaction solution was poured into water, neutralized withcitric acid, and then extracted with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate and then concentrated underreduced pressure to obtain 2.16 g of 6-tert-butoxynicotinic acid.

Production Example 11

To a mixed liquid of 2163 mg of 6-tert-butoxynicotinic acid and 32 ml ofacetone were added 2297 mg of potassium carbonate and 0.97 ml of methyliodide, followed by stirring at 35° C. overnight. Ethyl acetate andwater were added thereto to carry out liquid separation, and the organiclayer was dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure to obtain 1.191 g of methyl6-tert-butoxynicotinate.

Production Example 12

To a mixed liquid of 1191 mg of methyl 6-tert-butoxynicotinate and 35.7ml of ethanol was slowly added 2153 mg of sodium borohydride, followedby stirring at 50° C. for 18 hours. After the addition of methanol,water and ethyl acetate were added thereto to carry out an extractionoperation. The organic layer was dried over anhydrous magnesium sulfateand then concentrated under reduced pressure to obtain 0.949 g of(6-tert-butoxypyridin-3-yl)methanol.

Production Example 13

To a mixed liquid of 1020 mg of5-[(aminooxy)methyl]-2-tert-butoxypyridine, which had been obtained byreacting (6-tert-butoxypyridin-3-yl)methanol and N-hydroxyphthalimide inaccordance with Production Example 8, and then carrying out the removalof phthalimide in accordance with Production Example 9, and 20 ml ofethyl acetate was added 1.3 ml of concentrated hydrochloric acid underice-cooling, followed by stirring for 30 minutes. The resulting solidwas separated by filtration, concentrated hydrochloric acid was furtheradded to the filtrate, and the precipitated solid was collected byfiltration to obtain 351 mg of 5-[(aminooxy)methyl]pyridin-2(1H)-onehydrochloride as a colorless solid.

Production Example 14

To a mixture of 659 mg of 1-(chloromethyl)-4-(methylsulfonyl)benzene and10 ml of DMSO were added 525 mg of N-hydroxyphthalimide and 445 mg ofpotassium carbonate, followed by stirring at 50° C. for 2 hours. Thereaction solution was cooled, water was then added thereto, and theprecipitated crystal was collected by filtration to obtain 685 mg of2-{[4-(methylsulfonyl)benzyl]oxy}-1H-isoindole-1,3(2H)-dione as a whitesolid.

Production Example 15

To a solution of 5.08 g of tert-butyl [4-(hydroxymethyl)phenoxy]acetateand 4.6 ml of triethylamine in 30 ml of dichloromethane was added 1.98ml of methanesulfonyl chloride under ice-cooling, followed by stirringfor 1 hour under ice-cooling. The reaction solution was poured intowater, followed by extraction with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was then evaporated. To a solution of the obtainedresidue in 40 ml of DMF was added 4.26 g of sodium azide, followed bystirring at 60° C. for 15 hours. After leaving it to be cooled, thereaction solution was poured into water, followed by extraction withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasthen evaporated. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate-hexane) to obtain 5.16 g oftert-butyl [3-(azidomethyl)phenoxy]acetate as a pale yellow oilysubstance.

Production Example 16

To a mixed liquid of 5.00 g of methyl 5-formylthiophene-3-carboxylateand 50 ml of THF was added 0.67 g of sodium borohydride underice-cooling. To the reaction solution was added dropwise 5 ml ofmethanol, followed by stirring for 1 hour under ice-cooling. Thereaction solution was added with 1 M hydrochloric acid, extracted withethyl acetate, and washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. Theorganic layer was dried over anhydrous magnesium sulfate and the solventwas then evaporated to obtain 4.86 g of methyl5-(hydroxymethyl)thiophene-3-carboxylate as a pale yellow oilysubstance.

Production Example 17

To a mixed liquid of 4.86 g of methyl5-(hydroxymethyl)thiophene-3-carboxylate and 50 ml of dichloromethanewas added 4.12 ml of thionyl chloride under ice-cooling, followed bystirring at room temperature for 15 hours. The reaction solution wasconcentrated, added with ethyl acetate, and then washed with a saturatedaqueous sodium hydrogen carbonate solution and a saturated aqueoussodium chloride solution. After drying over anhydrous magnesium sulfate,the solvent was then evaporated to obtain 4.90 g of methyl5-(chloromethyl)thiophene-3-carboxylate as a pale yellow oily substance.

Production Example 18

To a solution of 3.69 g of di-tert-butyl imidodicarbonate in 54 ml ofDMF was added 1.91 g of potassium tert-butoxide at 0° C. under argon,followed by stirring at room temperature for 1 hour. A solution of 2.7 gof methyl 5-(chloromethyl)thiophene-3-carboxylate in 8.1 ml of DMF wasslowly added thereto, followed by stirring at room temperatureovernight. Water and ethyl acetate were added to the reaction solution,followed by carrying out an extraction operation, and the organic layerwas washed with a saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate) to obtain 4.394 g of methyl5-{[bis(tert-butoxycarbonyl)amino]methyl}thiophene-3-carboxylate.

Production Example 19

To a mixed liquid of 400 mg of ethyl difluoro(3-methylphenyl) acetateand 10 ml of carbon tetrachloride were added 349 mg ofN-bromosuccinimide and 15 mg of 2,2′-azobis(isobutyronitrile), followedby heating under reflux for 2 hours. After cooling the reactionsolution, the insoluble material was separated by filtration, and thefiltrate was concentrated. The residue was added with hexane, washedwith a saturated aqueous sodium hydrogen carbonate solution and asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. After evaporating the solvent, the residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate) to obtain 458 mg of ethyl [3-(bromomethyl)phenyl](difluoro)acetate as a colorless oily substance.

Production Example 20

To a mixed liquid of 2.89 g of ethyl2-methyl-2-(3-methylphenyl)propionate and 90 ml of carbon tetrachloridewere added 4.98 g of N-bromosuccinimide and 115 mg of2,2′-azobis(isobutyronitrile), followed by stirring at 80° C. for 2hours, and 4.98 g of N-bromosuccinimide and 115 mg of2,2′-azobis(isobutyronitrile) were further added thereto, followed bystirring at 80° C. for 14 hours. After cooling the reaction solution,the insoluble material was separated by filtration, and the solvent wasevaporated. To the residue was added hexane and followed by washing witha saturated aqueous sodium hydrogen carbonate solution and a saturatedaqueous sodium chloride solution. The organic layer was dried overanhydrous magnesium sulfate and the solvent was then evaporated toobtain 6.0 g of a pale yellow oily substance. The obtained oilysubstance was dissolved in 30 ml of THF, and 21.7 ml of diethylphosphite and 29.3 ml of diisopropylethylamine were added thereto underice-cooling, followed by stirring at room temperature for 13 hours. Thereaction solution was poured into ice water, followed by extraction withhexane. The organic layer was washed with 1 M hydrochloric acid and asaturated aqueous sodium chloride solution. After drying over anhydrousmagnesium sulfate, the solvent was evaporated, and the residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate) to obtain 2.95 g of ethyl2-[3-(dibromomethyl)phenyl]-2-methylpropionate as a pale yellow oilysubstance.

Production Example 21

To a mixed liquid of 2.95 g of ethyl2-[3-(dibromomethyl)phenyl]-2-methylpropionate and 30 ml of acetic acidwas added 4.77 g of potassium acetate, followed by stirring at 100° C.for 6 hours. After cooling the reaction solution, 10 ml of 6 Mhydrochloric acid was added thereto, followed by stirring at roomtemperature for 2 hours. The reaction solution was poured into water,followed by extraction with hexane, and the organic layer was washedwith water and a saturated aqueous sodium chloride solution. The organiclayer was dried over anhydrous magnesium sulfate and the solvent wasthen evaporated to obtain 1.74 g of ethyl2-(3-formylphenyl)-2-methylpropionate as a colorless oily substance.

Production Example 22

To a mixed liquid of 1.00 g of tert-butyl piperidin-4-ylcarbamate and 20ml of pyridine was added 0.77 ml of methanesulfonyl chloride, followedby stirring at room temperature for 18 hours. After evaporating thepyridine under reduced pressure, ethyl acetate was added thereto,followed by washing with a 5% aqueous citric acid solution, a saturatedaqueous sodium hydrogen carbonate solution, and a saturated aqueoussodium chloride solution. After drying the organic layer over anhydrousmagnesium sulfate, the solvent was evaporated, and the obtained solidwas washed with diethyl ether to obtain 1.19 g of t-butyl[1-(methylsulfonyl)piperidin-4-yl]carbamate as a white solid.

Production Example 23

To a solution of 1 g of tert-butyl [3-(cyanomethyl)phenoxy]acetate in 20ml of THF and 10 ml of methanol was added dropwise a suspension of 1.31g of cobalt chloride and 20 ml of water, and then 459 mg of sodiumborohydride was portionwise added thereto at room temperature. Afterstirring at room temperature for 10 minutes, the insoluble material wasseparated by filtration over Celite, washed with methanol, and thenconcentrated. The obtained residue was extracted with chloroform, anddried over anhydrous magnesium sulfate, and the solvent was thenevaporated. The obtained residue was purified by silica gel columnchromatography (eluent: chloroform-methanol-saturated aqueous ammonia)to obtain 632 mg of tert-butyl [3-(2-aminoethyl)phenoxy]acetate as apale yellow oily substance.

Production Example 24

To a mixed liquid of 5.16 g of t-butyl [3-(azidomethyl)phenoxy]acetateand 50 ml of THF were added 6.17 g of triphenylphosphine and 1.04 ml ofwater, followed by stirring at room temperature for 4 days. The solventwas evaporated and diisopropyl ether was added thereto. The precipitatedsolid was separated by filtration and the solvent was evaporated again.The residue was purified by silica gel column chromatography (eluent:chloroform-methanol-saturated aqueous ammonia) to obtain 4.10 g oft-butyl [3-(aminomethyl)phenoxy]acetate as a pale yellow oily substance.

Production Example 25

To a mixed liquid of 2.00 g of(1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid and40 ml of dichloromethane were added 1.41 ml of2-(trimethylsilyl)ethanol, 0.40 g of DMAP, and 2.21 g of WSC in thisorder, followed by stirring at room temperature for 60 hours. Afterevaporating the solvent, ethyl acetate was added thereto, followed bywashing with water, a 5% aqueous citric acid solution, a saturatedaqueous sodium hydrogen carbonate solution, and a saturated aqueoussodium chloride solution in this order. The organic layer was dried overanhydrous magnesium sulfate and the solvent was then evaporated toobtain 2.82 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate as acolorless oily substance.

Production Example 26

To a solution of 2.82 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-[(t-butoxycarbonyl)amino]cyclohexanecarboxylate in 10 ml ofethyl acetate, were added 20 ml of 4 M hydrogen chloride/ethyl acetateunder ice-cooling, followed by stirring at room temperature for 6 hours.The reaction solution was evaporated to obtain 2.30 g of2-(trimethylsilyl)ethyl (1RS,2SR)-2-aminocyclohexanecarboxylate as acolorless amorphous substance.

Production Example 27

To a mixed liquid of 4.40 g ofN-[(benzyloxy)carbonyl]-3-[(methylsulfonyl)amino]-D-alanine methylester, 100 ml of THF, and 50 ml of ethanol was added 1.13 g of lithiumchloride, and 1.01 g of sodium borohydride was further added theretounder ice-cooling. The reaction solution was stirred at room temperaturefor 14 hours, and the solvent was then evaporated under reducedpressure. After adding 150 ml of water, concentrated hydrochloric acidwas added thereto until the pH reached 2 to 3. The solution wasextracted with ethyl acetate, washed with a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated to obtain 3.10 g of benzyl[(1R)-2-hydroxy-1-{[(methylsulfonyl)amino]methyl}ethyl]carbamate as awhite solid.

Production Example 28

To a mixed liquid of 3.10 g of benzyl[(1R)-2-hydroxy-1-{[(methylsulfonyl)amino]methyl}ethyl]carbamate and 50ml of ethanol was added 500 mg of 5% palladium/carbon, followed bystirring at room temperature for 2 hours under a hydrogen atmosphere.The palladium/carbon was separated by filtration and the solvent wasthen evaporated to obtain 1.72 g ofN-[(2R)-2-amino-3-hydroxypropyl]methanesulfonamide as a colorless oilysubstance.

Production Example 29

To 700 mg of 2-(6-methoxypyridin-2-yl)ethylamine was added 10 ml of a47% aqueous hydrogen bromide solution, followed by stirring at 80° C.for 60 hours. After evaporating the solvent, the residue was washed withdiethyl ether to obtain 1.21 g of a 6-(2-aminoethyl)pyridin-2(1H)-onehydrobromide as a pale brown solid.

Production Example 30

A mixture of 3980 mg of2-[2-(1H-tetrazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione, 0.90 g ofhydrazine monohydrate, and 80 ml of ethanol was stirred at 70° C. for 12hours. The reaction solution was left to be cooled and the insolublematerial was then collected by filtration. The filtered material wassuspended in dioxane and 3.57 g of di-tert-butyl dicarbonate was addedthereto at room temperature, followed by stirring for 12 hours. Theinsoluble material was separated by filtration and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography using hexane/ethyl acetate as aneluent solvent to obtain 2210 mg of tert-butyl[2-(1H-tetrazol-1-yl)ethyl]carbamate as a colorless solid.

Production Example 31

To a solution of 2.62 g of tert-butyl 1H-pyrrole-3-carboxylate and 7.96g of N-(2-bromoethyl)phthalimide in DMF (100 ml) was added 10.2 g ofcesium carbonate at room temperature, followed by stirring for 12 hours.The reaction solution was diluted with water and extracted with ethylacetate. The extract was washed with saturated brine and then dried overanhydrous magnesium sulfate. The organic layer was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography using hexane/chloroform as an eluent solvent, and washedwith diethyl ether to obtain 670 mg of tert-butyl1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrrole-3-carboxylateas a colorless solid.

Production Example 32

A mixture of 660 mg of tert-butyl1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrrole-3-carboxylate,194 mg of hydrazine monohydrate, and 19 ml of ethanol was stirred at 70°C. for 12 hours. The reaction solution was left to be cooled and theinsoluble material was then separated by filtration. The filtrate wasconcentrated under reduced pressure to obtain 430 mg of tert-butyl1-(2-aminoethyl)-1H-pyrrole-3-carboxylate as a yellow oily substance.

Production Example 33

To a solution of 8.75 g of 2,4-dichlorobenzaldehyde in 100 ml ofchloroform were added 5.11 g of cyclopentylamine and 5 g of MolecularSieves 4A, followed by stirring at room temperature overnight. Afterremoving the Molecular Sieves 4A by filtration, 6.48 g of homophthalicanhydride was added thereto, followed by stirring at room temperatureovernight and then reflux for 5 hours. After concentrating under reducedpressure, ethyl acetate and a 1 M aqueous sodium hydroxide solution wereadded thereto to carry out a liquid separation operation. The aqueouslayer was acidified by the addition of 1 M hydrochloric acid, followedby extraction with chloroform-isopropyl alcohol (3:1). The organic layerwas washed with a saturated aqueous sodium chloride solution and driedover anhydrous sodium sulfate, and the solvent was then evaporated underreduced pressure. The obtained residue was added with ether andcollected by filtration to obtain 4.48 g of3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid (Production Example 33-1) as a colorless crystal. The mother liquidwas concentrated to obtain 6.46 g of3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid (Production Example 33-2) as a colorless amorphous substance.

Production Example 34

To a mixed solution of 2,4-dichlorobenzaldehyde in chloroform-methanolwere added trans-2-aminocyclohexanol, triethylamine, and anhydroussodium sulfate at room temperature, the reaction solution was stirred at50° C. overnight, and homophthalic anhydride was then added thereto atroom temperature, followed by stirring at room temperature overnight.After removing sodium sulfate by filtration, chloroform and a 1 Maqueous sodium hydroxide solution were added thereto to carry out aliquid separation operation, and the aqueous layer was stirred at roomtemperature for 2 hours. It was acidified by the addition of 1 Mhydrochloric acid, and ethyl acetate was added thereto to carry out aliquid separation operation. The organic layer was washed with asaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate, and then evaporated under reduced pressure. To the residue wasadded diethyl ether, followed by stirring at room temperature overnight.The precipitated crystal was collected by filtration to obtain 7655 mgof3RS,4RS-3-(2,4-dichlorophenyl)-2-(1SR,2SR-2-hydroxycyclohexyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid (Production Example 34-1) as a colorless crystal. Afterconcentrating the mother liquid, the residue was purified by silica gelcolumn chromatography (eluent: chloroform:methanol) to obtain 6600 mg of3SR,4SR-3-(2,4-dichlorophenyl)-2-(1RS,2RS-2-hydroxycyclohexyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid (Production Example 34-2) as a colorless crystal.

Production Example 35

To 4.33 g of(3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid were added 50 ml of ethanol and 2 ml of concentrated sulfuric acid,followed by heating under reflux overnight. Ethyl acetate and water wereadded thereto to carry out a liquid separation operation, and theorganic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. Theorganic layer was dried over anhydrous sodium sulfate and thenevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate) to obtain 2.3 gof ethyl(3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylateas a yellow foam.

Production Example 36

To a solution of 2.25 g of ethyl(3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylatein 30 ml of acetonitrile were added 0.75 ml of methanesulfonyl chlorideand 1.6 ml of diisopropylethylamine, followed by stirring at roomtemperature overnight. Ethyl acetate and water were added thereto tocarry out a liquid separation operation, and the organic layer waswashed with a saturated aqueous sodium chloride solution. The organiclayer was dried over anhydrous sodium sulfate, and then evaporated underreduced pressure. The residue was added with diethyl ether forcrystallization, and collected by filtration to obtain 2.02 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylateas a colorless crystal.

Production Example 37

To a solution of 1.4 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylatein 20 ml of DMF was added 229 mg of sodium hydride under ice-cooling,followed by stirring at the same temperature for 10 minutes, and then0.17 ml of methyl iodide was added thereto, followed by stirring underice-cooling for 30 minutes. Water was added thereto, followed byextraction with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution and dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 545 mg of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[methyl(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylateas a colorless amorphous substance.

Production Example 38

To a mixture of 2.0 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate,10 ml of methanol, and 10 ml of THF was added 10 ml of a 1 M aqueoussodium hydroxide solution, followed by stirring at room temperature for1 hour. The solution was acidified by the addition of 1 M hydrochloricacid, and then extracted with ethyl acetate. The organic layer waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to obtain 1.9 g of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid as a pale yellow crystal.

Production Example 39

A mixture of 8 g of 4-(benzyloxy)-2-(carboxymethyl)benzoic acid and 30ml of acetyl chloride was heated under reflux for 3 hours. The reactionsolution was concentrated under reduced pressure, added with ether, andcollected by filtration to obtain 7.50 g of6-(benzyloxy)-1H-isochromene-1,3(4H)-dione as a dark brown solid.

Production Example 40

To 612 mg of 6-[(aminooxy)methyl]pyridin-2(1H)-one, which had beenprepared by subjecting2-[(6-oxo-1,6-dihydropyridin-2-yl)methoxy-1H-isoindole-1,3(2H)dione toremoval of phthalimide in accordance with Production Example 9, wasadded 1.6 ml of a 4 M hydrogen chloride/ethyl acetate solution, and theprecipitated solid was collected by filtration to obtain 263 mg of6-[(aminooxy)methyl]pyridin-2(1H)-one hydrochloride as a colorlesssolid.

Production Example 41

To 2.04 g of (4-methyl-1H-imidazol-5-yl)methanol hydrochloride was added20 ml of acetonitrile, and 2.1 ml of triethylamine, 3.14 g ofdi-tert-butyl dicarbonate, and 0.17 g of DMAP were added thereto underice-cooling, followed by stirring at room temperature. Afterconcentrating the reaction solution under reduced pressure, ethylacetate and water were added thereto to carry out a liquid separationoperation, and the organic layer was washed with a saturated aqueoussodium chloride solution. The organic layer was dried over anhydroussodium sulfate, and then evaporated under reduced pressure. The obtainedresidue was reacted with N-hydroxyphthalimide in accordance withProduction Example 14, reacted with methylamine in accordance withProduction Example 9, and then subjected to deprotection of a Boc groupin accordance with Production Example 26 to obtain 0.53 g of5-[(aminooxy)methyl]-4-methyl-1H-imidazole dihydrochloride as acolorless solid.

Production Example 42

To a solution of 529 mg of (5-fluoropyridin-2-yl)methanol and 0.64 ml oftriethylamine in 8 ml of dichloromethane was added 0.35 ml ofmethanesulfonyl chloride under ice-cooling, followed by stirring for 1hour under ice-cooling. The reaction solution was poured into water,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate, and thesolvent was then evaporated. The obtained residue was reacted withN-hydroxyphthalimide in accordance with Production Example 14 to obtain522 mg of 2-[(5-fluoropyridin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dioneas a white solid.

Production Example 43

To a mixture of 2.97 g of 4-(hydroxymethyl)phenol, 4.90 g of tert-butylbromoacetate, and 25 ml of DMF was added 4.96 g of potassium carbonateat room temperature, followed by stirring for 12 hours. To the reactionsolution was added water, followed by extraction with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was then evaporated. Theresidue was purified by silica gel column chromatography (eluent: ethylacetate-hexane) to obtain a pale yellow oily substance. This oilysubstance was subjected to methanesulfonylation in accordance withProduction Example 15, and then reacted with sodium azide to obtain 4.03g of tert-butyl [4-(azidomethyl)phenoxy]acetate as a pale yellow oilysubstance.

Production Example 44

To a solution of 1.63 g of ethyl(3RS,4RS)-2-[(1SR,2SR)-2-{[(3-chloropropyl)sulfonyl]amino}cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylatein 20 ml of THF was added 142 mg of sodium hydride, followed by stirringat 50° C. overnight. Ethyl acetate and water were added thereto to carryout a liquid separation operation. The organic layer was washed with asaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate, and then evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate) to obtain 466 mg of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(1,1-dioxidoisothiazolidin-2-yl)cyclohexyl]-1-oxo-tetrahydroisoquinoline-4-carboxylateas a colorless crystal.

Production Example 45

A solution of 5.0 g of 4-bromothiophene-2-carbaldehyde, 11.4 ml ofvinyltributyltin, and 3.6 g of tetrakistriphenylphosphine palladium in100 ml of toluene was heated at 110° C. for 4 hours under a sealed tubecondition. The organic layer was extracted with ethyl acetate and washedwith water. In addition, the organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate) to obtain 3.4 g of 4-vinylthiophene-2-carbaldehyde as a brownliquid.

Production Example 46

A solution of 5 g of methyl 1-methyl-1H-imidazole-5-carboxylate and 22.5g of paraformaldehyde in 50 ml of methanol was heated at 140° C. for 60hours under a sealed tube condition. The precipitate was removed byfiltration and the solution was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 4 g of methyl2-(hydroxymethyl)-1-methyl-1H-imidazole-5-carboxylate as a white solid.

Production Example 47

7.4 ml of phosphorous oxychloride was added dropwise to 8.1 ml of DMF at0° C., followed by warming to room temperature. To the solution wasadded ethyl 3-furanate, followed by warming to 126° C. and stirring for1 hour. After cooling to room temperature, the reaction solution waspoured into ice water. The organic layer was extracted with diethylether and washed with a saturated aqueous sodium carbonate solution. Inaddition, the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate) to obtain 850mg of ethyl 5-formyl-3-furnate as a yellow solid.

Production Example 48

To a mixed liquid of 1.51 g of potassium cyanide and 70 ml ofacetonitrile, 6.12 g of 1,4,7,10,13,16-hexaoxacyclooctadecane was added,followed by stirring for 2 hours. Thereafter, a solution of 5.00 g oftert-butyl 3-(chloromethyl)benzoate in 30 ml of acetonitrile was addedthereto, followed by stirring at room temperature for 18 hours. Thereaction solution was concentrated, diluted with diethyl ether-hexane(1:1), and then washed with water and a saturated aqueous sodiumchloride solution. After drying over anhydrous magnesium sulfate, thesolvent was evaporated, and the residue was purified by silica gelcolumn chromatography (eluent: hexane-ethyl acetate) to obtain 3.86 g oftert-butyl 3-(cyanomethyl)benzoate as a colorless oily substance.

Production Example 49

A solution of 2 g of (benzyloxy)acetic acid in 30 ml of DMF was cooledto 0° C., and 2.44 g of 1-(4-aminophenyl)ethanone, 294 mg of DMAP, and3.73 g of WSC/hydrochloride were added thereto, followed by stirring atroom temperature for 3 hours. Liquid separation was carried out withethyl acetate-1 M hydrochloric acid. The organic layer was washed with asaturated aqueous sodium hydrogen carbonate solution and a saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, and then concentrated under reduced pressure to obtain 3.12 gof N-(4-acetylphenyl)-2-(benzyloxy)acetamide.

Production Example 50

To a solution of 1.64 g of ethyl 2-(hydroxymethyl)isonicotinate in 32.8ml of dichloromethane were added 1.24 ml of dihydropyrane and 2.32 g ofpyridinium p-toluenesulfonate, followed by stirring overnight. Ethylacetate was added thereto, followed by washing with a saturated aqueousammonium chloride solution and a saturated aqueous sodium chloridesolution. The organic layer was dried over anhydrous magnesium sulfateand then concentrated under reduced pressure to obtain 2.4 g of ethyl2-[(tetrahydro-2H-pyran-2-yloxy)methyl]isonicotinate.

Production Example 51

To a solution of 1.8 g of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanoneoxime in 36 ml of methanol was added 500 mg of 10% palladium-carbon (50%wet) under an argon atmosphere, followed by stirring for 7 hours under ahydrogen atmosphere. After filtration through Celite, the filtrate wasevaporated under reduced pressure to obtain 1.5 g of[6-(1-aminoethyl)pyridin-2-yl]methanol.

Production Example 52

To a solution of 2.06 g of 3-amino-4-hydroxybenzoic acid in 20.6 ml ofTHF was added 4.81 g of CDI, followed by stirring at room temperaturefor 1 hour. The reaction mixture was added dropwise to a mixed liquid of3.06 g of sodium borohydride in 20.6 ml of THF and 8.26 ml of water,cooled to 0° C., which had been separately prepared, followed bystirring overnight. 1 M hydrochloric acid was added thereto, followed byextracting with ethyl acetate, and washing with a saturated aqueoussodium chloride solution. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure to obtain1.2 g of 5-(hydroxymethyl)-1,3-benzoxazol-2(3H)-one.

Production Example 53

To 5 g of diethylpyridine-2,4-dicarboxylate were added 50 ml of ethanoland 50 ml of dichloroethane, followed by ice-cooling. 932 mg of sodiumborohydride was added portionwise thereto, followed by stirring for 1hour under ice-cooling, and further at room temperature for 15 hours.After ice-cooling the reaction solution, 5 ml of 6 M hydrochloric acidwas added thereto, followed by stirring for 5 minutes and concentrating.A saturated aqueous sodium hydrogen carbonate solution was addedthereto, followed by extracting with chloroform-isopropanol (10:1) anddrying over anhydrous magnesium sulfate. After concentrating underreduced pressure, the residue was purified by silica gel columnchromatography (eluent: chloroform-methanol) to obtain 0.7 g of ethyl4-(hydroxymethyl)pyridine-2-carboxylate (Production Example 53-1) and1.6 g of ethyl 2-(hydroxymethyl)isonicotinate (Production Example 53-2),respectively.

Production Example 54

To 1.6 g of 1-(6-methoxypyridin-2-yl)ethanamine was added 23.7 ml of a47% aqueous hydrobromic acid solution, followed by stirring at 80° C.for 60 hours. After evaporating the solvent under reduced pressure, theresidue was washed with diethyl ether to obtain 2.95 g of6-(1-aminoethyl)pyridin-2(1H)-one hydrobromide as a pale brown solid.

Production Example 55

To a solution of 2.31 g of tert-butyl 1H-pyrazole-3-carboxylate and 6.98g of N-(2-bromoethyl)phthalimide in DMF (65 mL) was added 8.95 g ofcesium carbonate at room temperature, followed by stirring for 12 hours.The reaction solution was diluted with water, followed by extractionwith ethyl acetate. The extract was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (eluent:chloroform-hexane) to obtain 1.51 g of tert-butyl1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrazole-3-carboxylateas a colorless solid.

Production Example 56

To a mixture of 2.92 g of (2-hydroxyphenyl)acetonitrile, 4.71 g oftert-butyl bromoacetate and 110 mL of DMF was added 6.06 g of potassiumcarbonate at room temperature, followed by stirring for 12 hours. To thereaction solution was added water, followed by extraction with ethylacetate. The extract was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography using hexane/ethyl acetate as an eluentsolvent to obtain 5.29 g of tert-butyl [2-(cyanomethyl)phenoxy]acetateas a yellow oily substance.

Production Example 57

A mixture of 1.38 g of 6-(hydroxymethyl)pyridin-2(1H)-one, 2.15 g oftert-butyl bromoacetate, 3.07 g of silver oxide, and 33 mL of DMF wasstirred at room temperature for 12 hours, and then at 60° C. for 12hours. The insoluble material was separated by filtration and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with ethyl acetate, followed by washing with a saturated aqueoussodium chloride solution. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate) to obtain 1.92 g of tert-butyl{[6-(hydroxymethyl)pyridin-2-yl]oxy}acetate as a yellow oily substance.

Production Example 58

To a mixture of 1.00 g of 3-hydroxybenzaldehyde, 1.80 g of tert-butyl(R)-lactate, 2.58 g of triphenylphosphine, and 40 mL of THF was added1.71 g of diethyl azodicarboxylate at room temperature, followed bystirring for 12 hours. The reaction solution was diluted with ethylacetate, followed by washing with a 5% aqueous sodium hydrogen carbonatesolution. The organic layer was dried over anhydrous magnesium sulfateand then concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate) to obtain 1.49 g of tert-butyl(2S)-2-(3-formylphenoxyl)propanoate as a colorless oily substance.

To a solution of 1.48 g of tert-butyl(2S)-2-(3-formylphenoxyl)propanoate in methanol(30 mL) was added 0.48 gof sodium borohydride under ice-cooling, followed by stirring for 1hour. The reaction solution was diluted with ethyl acetate, added withwater, neutralized with 1 M hydrochloric acid, and extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure to obtain 1.38 g of tert-butyl(2S)-2-[3-(hydroxymethyl)phenoxy]propanoate as a colorless oilysubstance.

Production Example 59

A solution of 2.90 g of 1,3-phenylene diacetic acid, 3.00 g of4-methoxybenzylbromide, and 2.99 g of potassium hydrogen carbonate in 15mL of DMF was stirred at room temperature for 36 hours. To the reactionsolution was added water, followed by neutralization with 1 Mhydrochloric acid. The product was extracted with ethyl acetate and theorganic layer was dried over anhydrous magnesium sulfate. Afterconcentrating under reduced pressure, 4.72 g of a colorless oilysubstance was obtained. A mixture of the obtained colorless oilysubstance (4.72 g), 2.42 g of HOBt, 2.78 g of WSC hydrochloride, 3.99 gof ammonium chloride, 7.55 g of triethylamine, and 18 mL of DMF wasstirred at room temperature for 12 hours. The reaction solution wasdiluted with water and extracted with ethyl acetate. The organic layerwas washed with saturated brine and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate) to obtain4-methoxybenzyl[3-(2-amino-2-oxoethyl)phenyl]acetate as a colorlesssolid.

To a solution of 1.31 g of4-methoxybenzyl[3-(2-amino-2-oxoethyl)phenyl]acetate in pyridine (20 mL)was added 718 mg of methanesulfonyl chloride under ice-cooling, followedby stirring for 2 hours. The reaction solution was concentrated underreduced pressure. The residue was diluted with ethyl acetate and washedwith a 5% aqueous citric acid solution, a saturated aqueous sodiumhydrogen carbonate solution, and then a saturated aqueous sodiumchloride solution in this order. The organic layer was dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate) to obtain 1.25 g of4-methoxybenzyl[3-(cyanomethyl)phenyl]acetate as a yellow oilysubstance.

Production Example 60

A mixture of 5.05 g of 5-methyl-2-furanecarboxylic acid, 7.14 g of CDI,and 40 mL of DMF was stirred at 50° C. for 2 hours. To the reactionsolution were added 6.71 g of DBU and 6.53 g of 2-methyl-2-propanol atroom temperature, followed by stirring at 50° C. for 48 hours. Thereaction solution was concentrated under reduced pressure, and theobtained residue was diluted with diethyl ether and washed with a 5%aqueous ammonium chloride solution, a saturated aqueous sodium hydrogencarbonate solution, and then a saturated aqueous sodium chloridesolution in this order. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate) to obtain 2.82 g of tert-butyl5-methyl-2-furanecarboxylate as a yellow oily substance.

Production Example 61

To a solution of 1643 mg of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone in25 ml of ethanol was added 0.72 ml of a 50% aqueous hydroxylaminesolution, followed by stirring overnight. The reaction solution wasconcentrated under reduced pressure to obtain 1806 mg of1-[6-(hydroxymethyl)pyridin-2-yl]ethanone oxime as an amorphoussubstance.

Production Example 62

To a mixture of 2.06 g of tert-butyl({6-[(hydroxymethyl)pyridin-2-yl]oxy}acetate, 2.60 g oftriphenylphosphine, 2.70 g of phthalimide, and 40 mL of THF was added1.73 g of diethyl azodicarboxylate at room temperature, followed bystirring for 36 hours. To the reaction solution was added ethyl acetate,followed by washing with a 5% aqueous sodium hydrogen carbonatesolution. The organic layer was dried over anhydrous magnesium sulfateand then concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography to obtain 2.33 g of({6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]pyridin-2-yl}oxy)aceticacid as a colorless solid.

Production Example 63

To a mixture of 1266 mg of{2-[(tetrahydro-2H-pyrane-2-yloxy)methyl]pyridin-4-yl}methyl benzoateand 25 ml of methanol was added 1166 mg of pyridiniump-toluenesulfonate, followed by stirring for 2 hours. A saturatedaqueous sodium hydrogen carbonate solution and chloroform were addedthereto for extraction, and the organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure to obtain941 mg of [2-(hydroxymethyl)pyridin-4-yl]methyl benzoate as an amorphoussubstance.

Production Example Compounds 64 to 371 were prepared in the same manneras the methods of Production Examples 1 to 63 and the methods ofExamples to be described later, using each of the corresponding startingmaterials. The structures and the physicochemical data of ProductionExample Compounds are shown in Tables 14 to 69.

Example 1

To a solution of 808 mg of3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid, 0.3 ml of phenylethylamine, and 405 mg of HOBt in dichloromethane(20 ml) was added 576 mg of WSC hydrochloride at room temperature,followed by stirring for 2 hours. To the reaction solution was addedchloroform, and the organic layer was washed with water and a saturatedaqueous sodium chloride solution in this order, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(eluent: chloroform) to obtain 902 mg of3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless crystal.

Example 2

To a mixture of 202 mg of3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid and 5 ml of dichloromethane were added 0.055 ml of oxalyl chlorideand one drop of DMF under ice-cooling, followed by stirring at roomtemperature for 30 minutes. The reaction solution was concentrated underreduced pressure, and the obtained residue was dissolved in 5 ml of THF,and 0.13 ml of phenylethylamine and 0.07 ml of triethylamine were addedthereto, followed by stirring at room temperature for 2 hours. Thereaction solution was concentrated under reduced pressure, added withethyl acetate, and washed with water and a saturated aqueous sodiumchloride solution in this order. The organic layer was dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(eluent: chloroform), and the obtained crude product was then collectedby filtration using diethyl ether to obtain 127 mg of3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless crystal.

Example 3

To a mixture of 254 mg of3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-[2-(2-pyridinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 5 ml of dichloromethane was added 173 mg of m-chloroperbenzoic acidunder ice-cooling, followed by stirring at room temperature overnight.To the reaction solution was added chloroform, washed with a 10% aqueoussodium hydrogen sulfite solution and a saturated aqueous sodium chloridesolution in this order, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (eluent; chloroform-methanol) andthen recrystallized from ethanol to obtain 138 mg of3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-N-[2-(1-oxidopyridin-2-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless crystal.

Example 4

To 654 mg ofN-{[(3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}-β-alanineethyl ester were added 5 ml of THF, 2 ml of methanol, and 5 ml of a 1 Maqueous sodium hydroxide solution at room temperature, followed bystirring at 50° C. for 3 hours. After neutralization by the addition of1 M hydrochloric acid, ethyl acetate was added for extraction. Theorganic layer was washed with water and a saturated aqueous sodiumchloride solution in this order, dried over anhydrous sodium sulfate,and then evaporated under reduced pressure. The obtained white solid wasrecrystallized from ethyl acetate to obtain 294 mg ofN-{[(3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}-β-alanineas a colorless powdered crystal.

Example 5

To 410 mg of tert-butyl{2-[3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}carbamatewas added 4 ml of a 4 M hydrogen chloride/ethyl acetate solution,followed by stirring at room temperature for 2 hours. The solvent wasevaporated under reduced pressure, and chloroform and a 1 M aqueoussodium hydroxide solution were then added to carry out a liquidseparation operation. The organic layer was washed with a saturatedaqueous sodium chloride solution, dried over anhydrous sodium sulfate,and then evaporated under reduced pressure. The obtained residue wasrecrystallized from ethyl acetate-hexane to obtain 192 mg of2-(2-aminoethyl)-3-(2,4-dichlorophenyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless powdered crystal.

Example 6

To a solution of 537 mg of3,4-trans-2-(trans-4-aminocyclohexyl)-3-(2,4-dichlorophenyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 10 ml of dichloromethane were added 0.33 ml of an aqueous formalinsolution and 893 mg of sodium triacetoxyborohydride, followed bystirring at room temperature overnight. To the reaction solution wasadded a saturated aqueous sodium hydrogen carbonate solution, followedby extraction with chloroform. The organic layer was washed with asaturated aqueous sodium chloride solution and then dried over anhydroussodium sulfate, and the solvent was evaporated. The obtained residue waspurified by silica gel column chromatography (eluent:chloroform-methanol), and the obtained white solid was recrystallizedfrom ethyl acetate to obtain 82 mg of3,4-trans-3-(2,4-dichlorophenyl)-2-[trans-4-(dimethylamino)cyclohexyl]-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless crystal.

Example 7

To a solution of 2.03 g of3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid in 20 ml of THF was added 810 mg of CDI, followed by stirring underheating at 50° C. for 1 hour. After cooling to room temperature, amixture of 200 mg of sodium borohydride and 10 ml of water was addedthereto, followed by stirring at room temperature for 4 hours. Ethylacetate and water were added thereto to carry out a liquid separationoperation, and the organic layer was washed with a saturated aqueoussodium chloride solution, dried over sodium sulfate, and then evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: chloroform), and the obtained solid wasrecrystallized from ethyl acetate to obtain 255 mg of3,4-trans-2-cyclopentyl-3-(hydroxymethyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless crystal.

Example 8

To 304 mg of(3RS,4RS)—N-(benzyloxy)-3-(4-methyl-3-nitrophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewere added 10 ml of acetic acid and 560 mg of reduced iron, followed bystirring at 50° C. overnight. To the reaction solution was addedmethanol, followed by filtration through Celite, and after concentratingthe mother liquid, ethyl acetate and water were added thereto to carryout a liquid separation operation. The organic layer was washed with asaturated aqueous sodium hydrogen carbonate solution and a saturatedaqueous sodium chloride solution, dried over anhydrous sodium sulfate,and then evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: chloroform:methanol). Theobtained solid was made into hydrochloride using a 4 M hydrogenchloride/ethyl acetate solution, and recrystallized from isopropylalcohol to obtain 180 mg of(3RS,4RS)-3-(3-amino-4-methylphenyl)-N-(benzyloxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidehydrochloride as a pale yellow powdered crystal.

Example 9

To 393 mg of3,4-trans-2-cyclopentyl-3-(hydroxymethyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewere added 10 ml of THF and 44 mg of sodium hydride, followed bystirring at room temperature for 30 minutes. To the reaction mixture wasadded 161 mg of 4-chlorobenzylbromide, followed by stirring at roomtemperature overnight. To the reaction mixture were added ethyl acetateand water to carry out a liquid separation operation, and the organiclayer was washed with a saturated aqueous sodium chloride solution. Theorganic layer was dried over anhydrous sodium sulfate and thenevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform) and the obtained solidwas crystallized from ether-hexane, and collected by filtration toobtain 134 mg of3,4-trans-3-{[(4-chlorobenzyl)oxy]methyl}-2-cyclopentyl-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless powdered crystal.

Example 10

To a solution of 573 mg of(3RS,4RS)—N-(2-chloroethyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 10 ml of DMF were added 150 mg of sodium iodide and 340 mg of1H-pyrazole, followed by stirring at 100° C. for 24 hours. Ethyl acetateand water were added thereto to carry out a liquid separation operation,and the organic layer was washed with a saturated aqueous sodiumchloride solution, dried over anhydrous sodium sulfate, and thenevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform-methanol) to obtain acolorless crystal. The crystal was recrystallized from ethanol to obtain176 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[2-(1H-pyrazol-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless powdered crystal.

Example 11

To a mixture of 270 mg of(3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 5 ml of pyridine was added 0.11 ml of acetic anhydride, followed bystirring at room temperature for 2 hours. Ethyl acetate and water wereadded thereto to carry out a liquid separation operation, and theorganic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution,dried over anhydrous sodium sulfate, and then evaporated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: chloroform-methanol) to obtain a colorless crystal. Theobtained crystal was added with diethyl ether and collected byfiltration to obtain 55 mg of(3RS,4RS)-2-[(1SR,2SR)-2-acetamidecyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless powdered crystal.

Example 12

To a mixture of 538 mg of(3RS,4RS)-2-{(1SR,2SR)-2-aminocyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 2.5 ml of pyridine was added 0.15 ml of methanesulfonyl chloride,followed by stirring at room temperature for 6 hours. Ethyl acetate andwater were added thereto to carry out a liquid separation operation, andthe organic layer was washed with a 1 M aqueous hydrochloric acidsolution and a saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate, and then evaporated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:chloroform) and then recrystallized from ethyl acetate-hexane to obtain206 mg of(3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless powdered crystal.

Example 13

To a mixed liquid of 200 mg of(3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 40 ml of dimethoxyethane was added 357 mg of sulfamide, followed bystirring at 80° C. for 2 days. The reaction solution was concentrated,added with chloroform, and then washed with water. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was thenevaporated. The residue was purified by silica gel column chromatography(eluent: chloroform-methanol), crystallized from ethyl acetate, andcollected by filtration to obtain 62 mg of(3RS,4RS)-2-{(1SR,2SR)-2-[(aminosulfonyl)amino]cyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 14

To a mixed liquid of 269 mg of(3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 5 ml of chloroform was added 0.21 ml of dimethylsulfamoyl chloride,followed by stirring at room temperature for 15 hours, and further at60° C. for 24 hours. In addition, 500 mg of sodium carbonate was addedthereto, followed by stirring at 60° C. for 5 hours. In addition, 0.21ml of dimethylsulfamoyl chloride was added thereto, followed by stirringat 60° C. for 5 hours. After cooling the reaction solution, a liquidseparation operation was then carried out using water and chloroform.The organic layer was washed with 1 M hydrochloric acid, a saturatedaqueous sodium hydrogen carbonate solution, and a saturated aqueoussodium chloride solution, and dried over anhydrous magnesium sulfate.After evaporating the solvent, the residue was purified by silica gelcolumn chromatography (eluent: chloroform-methanol) to obtain acolorless amorphous substance. The obtained amorphous substance wascrystallized with ethyl acetate to obtain 99 mg of(3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-{[(dimethylamino)sulfonylamino]amino}cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 15

To a mixed liquid of 269 mg of(3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 20 ml of ethanol was added 53 mg of nitrourea, followed by heatingunder reflux for 1 hour. The reaction solution was cooled and thenconcentrated, and the residue was purified by silica gel columnchromatography (eluent: chloroform-methanol), then crystallized withacetonitrile, and collected by filtration to obtain 155 mg of(3RS,4RS)—N-(benzyloxy)-2-[(1SR,2SR)-2-(carbamoylamino)cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 16

To a mixed liquid of 269 mg of(3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 5 ml of DMF were added 58 mg of sodium carbonate and 119 mg ofmethyl ethanimidothioate hydrochloride, followed by stirring at 60° C.for 1 hour. Thereafter, while stirring at 60° C., 233 mg of sodiumcarbonate and 478 mg of methyl ethanimidothioate hydrochloride werefurther added in four divided portions every 1 hour. After cooling thereaction solution, water was added thereto, followed by extraction withchloroform-isopropyl alcohol (5:1). The organic layer was dried overanhydrous magnesium sulfate and then concentrated. The residue waspurified by silica gel column chromatography (eluent:chloroform-methanol-aqueous ammonia) and then crystallized with ethylacetate to obtain 113 mg of(3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(ethanimidoylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 17

644 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(2-methoxy-6-methylpyridin-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 1.92 g of pyridine hydrochloride were mixed, followed by warmingfrom room temperature to 200° C. over 15 minutes. The molten mixture wasleft to be cooled and then subjected to a liquid separation operationusing water and ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate, and the solvent was evaporated. The residue waspurified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 480 mg of a low polarity product and 146mg of a high polarity product. The low polarity product was crystallizedwith ethyl acetate to obtain 277 mg of(3RS,4RS)-2-[(1SR)-cyclohex-2-en-1-yl]-3-(2,4-dichlorophenyl)-N-[2-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide(Example 17-1) as a white crystal. The high polarity product wasrecrystallized with ethyl acetate-ethanol to obtain 85 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide(Example 17-2) as a white crystal.

Example 18

To a mixed liquid of 456 mg of(3RS,4RS)—N-[(3-cyanobenzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 15 ml of DMF was added 139 mg of sodium azide and subsequently 114mg of ammonium chloride at room temperature, followed by warming to 100°C. and stirring for 12 hours. The reaction solution was cooled to roomtemperature, then added with water, and extracted with chloroform. Afterdrying over anhydrous magnesium sulfate, the solvent was evaporated andthe residue was purified by silica gel column chromatography (eluent:chloroform-methanol). The crude purified product thus obtained wasrecrystallized with ethanol-water to obtain 171 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(2H-tetrazol-5-yl)benzyl]oxy-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 19

A mixture of 730 mg of tert-butyl(3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetate,5 ml of dichloroethane, and 5 ml of trifluoroacetic acid was stirred atroom temperature for 2 hours. The reaction solution was concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (eluent: chloroform-methanol). The crudepurified product thus obtained was recrystallized from ethyl acetate toobtain 184 mg of(3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)aceticacid as a colorless crystal.

Example 20

To a solution of 330 mg of3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoicacid in 5 ml of DMF was added 122 mg of CDI, followed by stirring atroom temperature for 30 minutes. To the reaction solution were added 71mg of methane sulfonamide and 0.11 ml of DBU, followed by stirring atroom temperature for 3 hours. To the reaction solution was added ethylacetate, followed by washing with 1 M hydrochloric acid and a saturatedaqueous sodium chloride solution. The organic layer was dried overanhydrous magnesium sulfate and the solvent was then evaporated. Theresidue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain a crude purified product. This wasrecrystallized with acetonitrile-water to obtain 273 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-N-({3-[(methylsulfonyl)carbamoyl]benzyl}oxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 21

To a solution of 128 mg of(3RS,4RS)—N-(cyanomethoxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 1.92 ml of methanol was added 0.018 ml of a hydroxylamine solution atroom temperature, followed by warming to 40° C. and stirring overnight.The reaction solution was cooled to room temperature and theprecipitated crystal was then collected by filtration to obtain 26 mg of(3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 22

To a mixed liquid of 300 mg of(3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 30 ml of acetonitrile were added 132 mg of 1,1′-carbonothioylbis(1H-imidazole) and 0.27 ml of DBU under ice-cooling, followed bystirring at room temperature for 1 hour. The reaction solution wasconcentrated and then added with 50 ml of water, and 1 M hydrochloricacid was added thereto until the pH reached 4 to 5. After extractingwith ethyl acetate, washing with a saturated aqueous sodium chloridesolution and drying over anhydrous magnesium sulfate, the solvent wasevaporated. The residue was purified by silica gel column chromatography(eluent: chloroform-methanol). The crude purified product thus obtainedwas added with ethyl acetate and collected by filtration to obtain 61 mgof(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white solid.

Example 23

To a mixed liquid of 280 mg of(3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 10 ml of DMF were added 0.037 ml of pyridine and subsequently 0.084ml of 2-ethylhexyl chloroformate under ice-cooling, followed by stirringunder ice-cooling for 30 minutes. To the reaction solution was addedethyl acetate, followed by washing with water and a saturated aqueoussodium chloride solution. The organic layer was dried over anhydrousmagnesium sulfate and the solvent was then evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (eluent: chloroform-methanol) to obtain 305 mg of(3RS,4RS)—N-[(3-{amino[({[(2-ethylhexyl)oxy]carbonyl}oxy)imino]methyl}benzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white amorphous substance. To 290 mg of the present compound wasadded 6 ml of NMP, followed by stirring at 140° C. for 3 hours. Thereaction solution was cooled, and 50 ml of water was then added thereto,followed by stirring. The precipitated solid was collected byfiltration. This solid was purified by silica gel column chromatography(eluent: chloroform-methanol), then crystallized withacetonitrile-water, and collected by filtration to obtain 101 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 24

To a solution of 500 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[(1-trityl-1H-1,2,4-triazol-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 7.5 ml of methanol was added dropwise 0.25 ml of concentratedhydrochloric acid under ice-cooling, followed by stirring at roomtemperature for 4 hours. To the reaction solution was added a saturatedaqueous sodium hydrogen carbonate solution, followed by extraction withchloroform. The organic layer was dried over anhydrous magnesium sulfateand then concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) and recrystallized from ethyl acetate to obtain 282mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(1H-1,2,4-triazol-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless crystal.

Example 25

A solution of 400 mg of(3RS,4RS)-6-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 245 mg of pentamethylbenzene in 15 ml of trifluoroacetic acid wasstirred at room temperature overnight. The trifluoroacetic acid wasevaporated under reduced pressure, and ethyl acetate and water wereadded thereto to carry out a liquid separation operation. The organiclayer was washed with a saturated aqueous sodium chloride solution,dried over anhydrous sodium sulfate, and then evaporated under reducedpressure. The residue was solidified with ethyl acetate-isopropylalcohol and collected by filtration to obtain 350 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-6-hydroxy-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white solid.

Example 26

To a solution of 644 mg of(3RS,4RS)—N-[(4-tert-butoxybenzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 8.4 ml of dichloromethane was added 0.94 ml of trifluoroacetic acidunder ice-cooling, followed by stirring at room temperature for 1 hour.The solution was concentrated under reduced pressure and thenrecrystallized from ethyl acetate to obtain 363 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-N-hydroxy-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless crystal.

Example 27

To a mixed liquid of 350 mg of ethyl1,2-cis-2-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylate,25 ml of THF, and 25 ml of ethanol was added 1 ml of a 1 M aqueoussodium hydroxide solution, followed by stirring at room temperature for60 hours, and further at 60° C. for 8 hours. After evaporating thesolvent, a liquid separation operation was carried out using 1 Mhydrochloric acid and chloroform. The organic layer was dried overanhydrous magnesium sulfate and the solvent was then evaporated. Theresidue was purified by silica gel column chromatography (eluent:chloroform-methanol). The obtained residue was washed with diisopropylether-ethyl acetate to obtain 144 mg of ethyl1,2-trans-2-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylateas a white solid.

Example 28

To a mixed liquid of 334 mg of 2-(trimethylsilylethyl)1,2-cis-2-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(pyridin-2-ylmethoxy)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylateand 5 ml of THF was added 0.60 ml of a 1 M solution oftetrabutylammonium fluoride in THF, followed by stirring at roomtemperature for 4 hours. To the reaction solution was added 20 ml ofDMF, followed by stirring at room temperature for 2 hours, thenevaporating the THF under reduced pressure, and stirring again at roomtemperature for 20 hours. The reaction solution was warmed to 60° C. andstirred for 2 hours, and then 0.30 ml of a 1 M solution oftetrabutylammonium fluoride in THF was further added thereto, followedby stirring at 60° C. for 2 hours. After evaporating the solvent underreduced pressure, 1 M hydrochloric acid was added, and a 1 M aqueoussodium hydroxide solution was added thereto until the pH reached 2. Thesolution was extracted with ethyl acetate and chloroform, and dried overanhydrous magnesium sulfate, and the solvent was then evaporated. Theresidue was purified by silica gel column chromatography (eluent:chloroform-methanol), and the obtained residue was then washed withethyl acetate to obtain 156 mg of1,2-cis-2-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(pyridin-2-ylmethoxy)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylicacid as a white solid.

Example 29

To a solution of 1000 mg of(3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 26 ml of dichloroethane was added dropwise 0.4 ml of pyridine, andthen 0.23 ml of methyl chloro(oxo)acetate was added dropwise theretounder ice-cooling, followed by stirring at 0° C. for 10 minutes, at roomtemperature for 20 minutes, and at 80° C. for 2 hours. The reactionsolution was cooled to room temperature, washed with 0.1 M hydrochloricacid and a saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: chloroform-methanol) to obtain 670 mg of methyl3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazole-5-carboxylateas a white amorphous substance.

Example 30

To 400 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid were added 8 ml of DMF, 243 mg of O-[3-(tetrahydro-2H-pyran-2-yloxy)benzyl]hydroxylamine, 159 mg of HOBt, and 243 mg of WSC, followed bystirring at room temperature for 3 hours. The reaction solution wasadded with ethyl acetate and water to carry out a liquid separationoperation, and the organic layer was washed with a saturated aqueoussodium hydrogen carbonate solution and a saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, and thenevaporated under reduced pressure. To the residue was added methanol,and concentrated hydrochloric acid was added dropwise thereto underice-cooling, followed by stirring under ice-cooling for 1 hour. Theprecipitated crystal was collected by filtration to obtain 275 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(3-hydroxybenzyl)oxy]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 31

To a solution of 323 mg of(3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)methylacetate in 6.5 ml of methanol was added 66 mg of potassium carbonate,followed by stirring at room temperature for 3 hours. To the reactionsolution was added ethyl acetate, followed by washing with a saturatedaqueous sodium chloride solution. The organic layer was dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: chloroform-methanol) and then recrystallized from ethyl acetateto obtain 157 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 32

By condensing4-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)butanoicacid and ethylamine using WSC and HOBt in accordance with Example 1,(3RS,4RS)-3-(2,4-dichlorophenyl)-N-[4-(ethylamino)-4-oxobutyl]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewas obtained as a colorless crystal.

Example 33

By condensing3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid and benzylamine using WSC and HOBt in accordance with Example1,3,4-trans-3-benzylcarbamoyl-2-cyclopentyl-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewas obtained as a colorless crystal.

Example 34

By condensingcis-4-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylicacid and 1-methylpiperazine using WSC and HOBt in accordance withExample 1,3,4-trans-3-(2,4-dichlorophenyl)-2-{cis-4-[(4-methylpiperazin-1-yl)carbonyl]cyclohexyl}-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewas obtained as a colorless crystal.

Example 35

By condensing(3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand hydroxyacetic acid using WSC and HOBt in accordance with Example 1,(3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(glycoloylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewas obtained as a colorless crystal.

Example 36

By treating3,4-trans-2-cyclopentyl-3-(3-pyridinyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewith m-chloroperbenzoic acid in accordance with Example3,3,4-trans-2-cyclopentyl-3-(1-oxidopyridin-3-yl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewas obtained as a colorless crystal.

Example 37

By treating3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-2-[2-(3-pyridinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewith m-chloroperbenzoic acid in accordance with Example 3,3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-2-[2-(1-oxidopyridin-3-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewas obtained as a colorless crystal.

Example 38

By treating methyl4-{3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinolin-3-yl}benzoatewith a 1 M aqueous sodium hydroxide solution in accordance with Example4,4-{3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinolin-3-yl}benzoicacid was obtained as a colorless crystal.

Example 39

By treating ethyl4-{3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}propanoatewith a 1 M aqueous sodium hydroxide solution in accordance with Example4,4-{3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}propanoicacid was obtained as a colorless crystal.

Example 40

By treating4-{[({[(3RS,4RS)-trans-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-trans-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoicacid with CDI and then with sodium borohydride in accordance withExample 7,(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-1,2-trans-2-hydroxycyclohexyl]-N-{[4-(hydroxymethyl)benzyl]oxy}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidewas obtained as a colorless crystal.

Example 41

To a mixed liquid of 400 mg of(3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideand 40 ml of acetonitrile were added 108 mg of CDI and 0.4 ml of DBUunder ice-cooling, followed by stirring at room temperature overnight.After concentrating the reaction solution, a saturated aqueous ammoniumchloride solution and ethyl acetate were added thereto, followed byextraction. The organic layer was washed with saturated brine and thendried over anhydrous magnesium sulfate, and the solvent was evaporated.The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) and recrystallized from ethyl acetate to obtain 40mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless crystal.

Example 42

To a mixture of 300 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid and 6 ml of DMF were added {5-[(aminooxy)methyl]pyrazin-2-yl}methylacetate dihydrochloride, 0.16 ml of triethylamine, 119 mg of HOBt, and200 mg of WSC, followed by stirring at room temperature for 3 hours.Ethyl acetate and water were added thereto to carry out a liquidseparation operation. The organic layer was washed with a saturatedaqueous sodium hydrogen carbonate solution and saturated brine, driedover anhydrous magnesium sulfate, and then evaporated under reducedpressure. To the residue were added 4.5 ml of methanol and 2.4 ml of a 1M aqueous sodium hydroxide solution, followed by stirring at 0° C. for 2hours, and then 1 M hydrochloric acid was added thereto forneutralization. Chloroform was added thereto for extraction, and theorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluent: chloroform-methanol) and then recrystallizedfrom ethyl acetate to obtain 73 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)pyrazin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless crystal.

Example 43

To a solution of 350 mg of(3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 9.2 ml of dichloroethane was added dropwise 0.15 ml of pyridine. Tothe reaction solution was added dropwise 0.095 ml of 2-chloro-2-oxoethylacetate under ice-cooling, followed by stirring for 10 minutes at 0° C.,20 minutes at room temperature and then heating under reflux for 8hours. The solution was cooled to room temperature, and ethyl acetatewas added thereto, followed by washing with 0.1 M hydrochloric acid anda saturated aqueous sodium chloride solution. The organic layer wasdried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: chloroform-methanol) to obtain 323 mg of(3-{[({[(3RS,4RS-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)methylacetate.

Example 44

To a solution of 600 mg of methyl5-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}thiophene-3-carboxylatein 40 mL of THF was added 45 mg of lithium aluminum hydride at −78° C.The solution was warmed to 0° C., followed by stirring for 3 hours.Sodium sulfate decahydrate was added thereto, followed by stirring for 1hour. After removing sodium sulfate by filtration, the organic layer wasdried by adding anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: chloroform-methanol) to obtain 162 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[4-(hydroxymethyl)-2-thienyl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white solid.

Example 45

To a solution of 500 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-6-nitro-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 10 ml of methanol-dioxane(1:1) was added 500 mg of Raney nickel,followed by stirring for 30 minutes under a hydrogen atmosphere. Thecatalyst was removed by filtration and the solvent was concentratedunder reduced pressure to obtain 300 mg of(3RS,4RS)-6-amino-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a black solid.

Example 46

To a solution of 300 mg of(3RS,4RS)-6-amino-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,213 mg of formaldehyde, and 11 mg of sulfuric acid in 5 ml of THF wasadded 125 mg of sodium borohydride at 0° C., followed by stirring for 2hours. The reaction solution was poured into ice water and the organiclayer was extracted with ethyl acetate. The solution was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by reverse-phase silica gel column chromatography(eluent: acetonitrile-water) to obtain 10 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-6-(dimethylamino)-2-{(1R,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a yellow solid.

Example 47

A solution of 343 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oxoethoxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 6.9 ml of THF was cooled to 0° C., and 116 mg of1,1′-carbonyldiimidazole and 0.12 ml of triethylamine were addedthereto, followed by stirring at 0° C. for 2 hours, and then stirring atroom temperature overnight. 0.1 M hydrochloric acid was added thereto,followed by extraction with ethyl acetate. The solution was washed witha saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and then concentrated under reduced pressure. Theresidue was recrystallized from ethyl acetate to obtain 221 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white powder crystal.

Example 48

To a mixed liquid of 420 mg of benzyl({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetate,5 ml of DMF, and 5 ml of ethanol was added 84 mg of 5% palladium/carbon,followed by stirring at room temperature for 15 minutes under a hydrogenatmosphere. After separating the palladium/carbon by filtration, thesolvent was evaporated, and the residue was purified by silica gelcolumn chromatography (eluent: chloroform-methanol) to obtain 78 mg of({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)aceticacid as a white solid.

Example 49

A solution of 480 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[6-(hydroxymethyl)pyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 4.8 ml of dichloromethane was cooled to 0° C., 4.5 mg of DMAP and0.13 ml of pyridine were added, and then 0.7 ml of acetic anhydride wasadded dropwise, followed by stirring at room temperature overnight. Tothe reaction mixture was added water, followed by extraction with ethylacetate. The organic layer was dried over anhydrous magnesium sulfateand then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (eluent: chloroform-methanol) toobtain (6-{[(acetyl{[3-(2,4-dichlorophenyl)-2-{2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}pyridin-2-yl)methylacetate.

Example 50

A solution of 714 mg of(3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)pyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 14.3 ml of chloroform was cooled to 0° C., and 0.23 ml oftriethylamine, 0.16 ml of acetic anhydride, and 6.8 mg of DMAP wereadded thereto in this order, followed by stirring at room temperaturefor 5 hours. The reaction solution was concentrated under reducedpressure, and ethyl acetate-water was added thereto for liquidseparation, followed by washing with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. Thesolution was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure to obtain{6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}methylacetate.

Example 51

To 591 mg of[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]aceticacid were added 8 ml of DMF, 200 mg of tert-butyl hydrazinecarboxylate,205 mg of HOBt, and 388 mg of WSC hydrochloride, followed by stirring atroom temperature for 3 hours. Ethyl acetate and water were added theretoto carry out a liquid separation operation. The organic layer was washedwith a saturated aqueous sodium hydrogen carbonate solution and asaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and then evaporated under reduced pressure. 7.7 ml ofdichloromethane was added thereto, followed by cooling to 0° C., and 1.2ml of trifluoroacetic acid was added thereto, followed by stirring atroom temperature for 5 hours. The residue was purified by silica gelcolumn chromatography (eluent: chloroform-methanol) and recrystallizedfrom ethyl acetate to obtain 417 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oxoethoxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white powder crystal.

Example 52

A solution of 153 mg of(6-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1-oxidopyridin-3-yl)methylbenzoate in 3 ml of ethanol was cooled to 0° C., and 32 mg of sodiumhydroxide was added thereto, followed by stirring at 0° C. for 2 hours.The solution was neutralized with 1 M hydrochloric acid, and a saturatedaqueous sodium hydrogen carbonate solution and chloroform were added forliquid separation. The organic layer was dried over anhydrous magnesiumsulfate and then evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 24 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1-oxidopyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.

Example 53

To a solution of 700 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid, 351 mg of 1-phenylmethanesulfonamide, and 334 mg of DMAP in 10.5ml of DMF was added 525 mg of WSC/hydrochloride, followed by stirring atroom temperature overnight. 0.1 M hydrochloric acid was added thereto,followed by extraction with ethyl acetate. The organic layer was washedwith a saturated aqueous sodium chloride solution, then dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:chloroform-methanol), and ethyl acetate and a saturated aqueous sodiumhydrogen carbonate solution were then added thereto for liquidseparation. The organic layer was dried over anhydrous magnesium sulfateand then concentrated under reduced pressure. Ethyl acetate anddiisopropyl ether were added thereto, and the precipitated solid wascollected by filtration to obtain 33 mg of(3RS,4RS)—N-(benzylsulfonyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless solid.

Example 54

To a solution of 566 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(2,2-dimethyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)methoxy]-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamidein 11.3 ml of THF was added 3.2 ml of 1 M hydrochloric acid, followed bystirring at room temperature for 2 hours. 1.6 ml of 1 M hydrochloricacid was further added, followed by stirring for 2 days. The solutionwas neutralized with a saturated aqueous sodium hydrogen carbonatesolution and then extracted with chloroform. The organic layer was driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: chloroform-methanol) and recrystallized from ethyl acetate toobtain 196 mg ofrel-(3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-hydroxy-6-(hydroxymethyl)pyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a white crystal.

Example 55

To a solution of 433 mg of6-{[(acetyl{[3-(2,4-dichlorophenyl)-2-{2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1-oxidopyridin-2-yl)methylacetate in 8.7 ml of methanol was added 160 mg of potassium carbonate,followed by stirring. The solution was added with 1 M hydrochloric acidand then with a saturated aqueous sodium hydrogen carbonate solution,extracted with ethyl acetate, dried over anhydrous magnesium sulfate,and then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (eluent: chloroform-methanol). Ethylacetate, ethanol, and diisopropyl ether were added thereto forsolidification to obtain 164 mg of3-(2,4-dichlorophenyl)-N-{[6-(hydroxymethyl)-1-oxidopyridin-2-yl]methoxy}-2-{2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless solid.

Example 56

To a solution of 777 mg of{6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]-1-oxidopyridin-2-yl}methylacetate in 17 ml of methanol was added 0.21 ml of hydrazine monohydrate,followed by stirring for one week. Ethyl acetate was added thereto,followed by stirring for a while and concentrating, and the residue waspurified by silica gel column chromatography (eluent:chloroform-methanol). Ethyl acetate and diisopropyl ether were used tomake a powder, thereby obtaining 501 mg of(3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)-1-oxidopyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless solid.

Example 57

A mixture of 590 mg of3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoicacid, 217 mg of CDI, and 9 ml of DMF was stirred at 50° C. for 1 hour,and 241 mg of guanidine carbonate was then added thereto, followed bystirring at the same temperature for 3 hours. The reaction solution wasleft to be cooled and the solvent was then evaporated under reducedpressure. The residue was diluted with ethyl acetate, and washed with asaturated aqueous sodium hydrogen carbonate solution and then with asaturated aqueous sodium chloride solution. The organic layer was driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (eluent: chloroform-methanol) and recrystallized fromacetonitrile to obtain 348 mg of(3RS,4RS)—N-({3-[(diaminomethylene)carbamoyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamideas a colorless solid.

Example 58

To a mixture of 990 mg of 4-methoxybenzyl(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetateand 10 ml of ethylene chloride was added 10 ml of trifluoroacetic acidat room temperature, followed by stirring for 4 hours. The reactionsolution was concentrated under reduced pressure. The residue wasdissolved in 20 mL of methanol, and 20 mL of a saturated aqueous sodiumhydrogen carbonate solution was added thereto at room temperature,followed by stirring for 30 minutes. The organic solvent was evaporatedunder reduced pressure, and the residue was diluted with ethyl acetateand neutralized with 1 M hydrochloric acid. The product was extractedwith ethyl acetate, and the organic layer was washed with a saturatedaqueous sodium chloride solution and then dried over anhydrous magnesiumsulfate. The organic layer was concentrated under reduced pressure, andthe obtained residue was purified by silica gel column chromatography(eluent: chloroform-methanol) to obtain 339 mg of(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)aceticacid as a colorless solid.

Example 59

To a mixture of 980 mg of(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(3-hydroxyphenyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,1160 mg of triphenylphosphine, 1080 mg of tert-butyl(2R)-2-hydroxypropanate, and 30 mL of THF was added 770 mg of diethylazodicarboxylate at room temperature, followed by stirring for 12 hours.The reaction solution was diluted with ethyl acetate and washed with asaturated aqueous sodium hydrogen carbonate solution. The organic layerwas dried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (eluent: chloroform-methanol) to obtain 1460 mg oftert-butyl(2S)-2-(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenoxy)propanateas a yellow solid.

The compounds of Examples 60 to 899 as shown in Tables below wereprepared in the same manner as the methods of Examples 1 to 59, usingeach of the corresponding starting materials. The structures of eachExample Compound are shown in Tables 70 to 275, and the productionprocesses and the physicochemical data of each Example Compound areshown in Tables 276 to 300.

Furthermore, the structures of the other compounds of the presentinvention are shown in Tables 301 to 302. These can be easilysynthesized by using the production processes as described above, themethods described in Examples, methods obvious to a skilled person inthe art, or modified methods thereof.

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Lengthy table referenced here US20150359787A1-20151217-T00024 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00025 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00026 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00027 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00028 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00029 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00030 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00031 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00032 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00033 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00034 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00035 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00036 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00037 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00038 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00039 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00040 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00041 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00042 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00043 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00044 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00045 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00046 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00047 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00048 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00049 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00050 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00051 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00052 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00053 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00054 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00055 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00056 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00057 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00058 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00059 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00060 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00061 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00062 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00063 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00064 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00065 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00066 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00067 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00068 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00069 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00070 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00071 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00072 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00073 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00074 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00075 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00076 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00077 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00078 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00079 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00080 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00081 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00082 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00083 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00084 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00085 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00086 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00087 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00088 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00089 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00090 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00091 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00092 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00093 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00094 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00095 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00096 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00097 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00098 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00099 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00100 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00101 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00102 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00103 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00104 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00105 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00106 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00107 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00108 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00109 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00110 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00111 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00112 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00113 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00114 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00115 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00116 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00117 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00118 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00119 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00120 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00121 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00122 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00123 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00124 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00125 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00126 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00127 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00128 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00129 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00130 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00131 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00132 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00133 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00134 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00135 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00136 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00137 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00138 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00139 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00140 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00141 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00142 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00143 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00144 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00145 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00146 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00147 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00148 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00149 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00150 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00151 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00152 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00153 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00154 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00155 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00156 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00157 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00158 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00159 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00160 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00161 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00162 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00163 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00164 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00165 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00166 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00167 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00168 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00169 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00170 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00171 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00172 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00173 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00174 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00175 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00176 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00177 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00178 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00179 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00180 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00181 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00182 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00183 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00184 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00185 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00186 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00187 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00188 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00189 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00190 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00191 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00192 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00193 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00194 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00195 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00196 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00197 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00198 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00199 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00200 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00201 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00202 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00203 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00204 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00205 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00206 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00207 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00208 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00209 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00210 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00211 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00212 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00213 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00214 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00215 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00216 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00217 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00218 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00219 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00220 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00221 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00222 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00223 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00224 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00225 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00226 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00227 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00228 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00229 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00230 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00231 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00232 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00233 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00234 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00235 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00236 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00237 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00238 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00239 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00240 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00241 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00242 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00243 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00244 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00245 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20150359787A1-20151217-T00246 Pleaserefer to the end of the specification for access instructions.

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INDUSTRIAL APPLICABILITY

The compound (I) of the present invention as described above is usefulas a therapeutic agent for the diseases in which BB2 receptors arerelated, in particular, for IBS since it has an excellent BB2 receptorantagonistic activity, and further, it exhibits excellent efficacyregarding bowel movement disorders.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20150359787A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A method of treating a cancer in a patient, comprising administeringto the patient suffering from a cancer a compound represented by theformula (I) or a pharmaceutically acceptable salt thereof:

in which groups R¹-R⁵ and m are as follows R¹: lower alkylene-OH, loweralkylene-N(R⁰)(R⁶), lower alkylene-CO₂R⁰, cycloalkyl, cycloalkenyl,aryl, heterocyclic group, -(lower alkylene substituted with —OR⁰)-arylor lower alkylene-heterocyclic group, wherein the lower alkylene,cycloalkyl, cycloalkenyl, aryl and heterocyclic group in R¹ may each besubstituted, R⁰: the same as or different from each other, eachrepresenting —H or lower alkyl, R⁶: R⁰, —C(O)—R⁰, —CO₂-lower alkyl or—S(O)₂-lower alkyl, R²: lower alkyl, lower alkylene-OR⁰, loweralkylene-aryl, lower alkylene-heterocyclic group, loweralkylene-N(R⁰)CO-aryl, lower alkylene-O-lower alkylene-aryl, —CO₂R⁰,—C(O)N(R)₂, —C(O)N(R⁰)-aryl,) —C(O)N(R⁰)-lower alkylene-aryl, or aryl,wherein the aryl and heterocyclic group in R² may each be substituted,R³: —H or lower alkyl, or R² and R³ may be combined to form C₂₋₆alkylene, R⁴: —N(R⁷)(R⁸), —N(R⁰)—OH, —N(R¹⁰)—OR⁷, —N(R⁰)—N(R⁰)(R⁷),—N(R⁰)—S(O)₂-aryl, or —N(R⁰)—S(O)₂—R⁷, wherein the aryl in R⁴ may besubstituted, R⁷: lower alkyl, halogeno-lower alkyl, lower alkylene-CN,lower alkylene-OR⁰, lower alkylene-CO₂R⁰, lower alkylene-C(O)N(R⁰)₂,lower alkylene-C(O)N(R⁰)N(R⁰)₂, lower alkylene-C(═NH)NH₂, loweralkylene-C(═NOH)NH₂, heteroaryl, lower alkylene-X-aryl, or loweralkylene-X-heterocyclic group, wherein the lower alkylene, aryl,heteroaryl, and heterocyclic group in R⁷ may each be substituted, X:single bond, —O—, —C(O)—, —N(R⁰), —S(O_(p)—, or *—C(O)N(R⁰)—, wherein *in X represents a bond to lower alkylene, m: an integer of 0 to 3, p: aninteger of 0 to 2, R⁸: —H or lower alkyl, or R⁷ and R⁸ may be combinedto form lower alkylene-N(R⁹)-lower alkylene, lower alkylene-CH(R⁹)-loweralkylene, lower alkylene-arylene-lower alkylene, or loweralkylene-arylene-C(O)—, R⁹: aryl and heteroaryl which may each besubstituted, R¹⁰: —H, lower alkyl, or —C(O)R⁰, R⁵: lower alkyl,halogeno-lower alkyl, halogen, nitro, —OR⁰, —O-halogeno-lower alkyl,—N(R⁰)₂, —O-lower alkylene-CO₂R⁰, or —O-lower alkylene-aryl, wherein thearyl in R⁵ may be substituted, provided that, when R⁴ is —N(R⁷)(R⁸), (1)a compound wherein R¹ is unsubstituted cyclopentyl and R² isunsubstituted 2-thienyl; (2) a compound wherein R¹ is unsubstitutedcyclohexyl and R² is 4-methoxyphenyl; (3) a compound wherein R¹ is4-methoxyphenyl and R² is 4-methoxyphenyl; and (4) a compound wherein R¹is (morpholin-4-yl)ethyl and R² is 4-ethoxyphenyl are excluded, andfurther provided that,2,3-bis(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,3-(4-chlorobenzyl)-2-(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-furylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,ethyl3-{3-[3,5-bis(trifluoromethyl)phenyl]-4-{[2-(4-methoxyphenyl)ethyl]carbamoyl}-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl}propanoate,N-benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-1-oxo-2-(tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methoxyethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,3-[3,5-bis(trifluoromethyl)phenyl]-2-(2-furylmethyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-furylmethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,and(4-chlorophenyl)[3-(4-chlorophenyl)-4-[(2-methoxyethyl)carbamoyl]-1-oxo-3-,4-dihydroisoquinolin-2(1H)-yl]aceticacid are excluded.
 2. The method according to claim 1, wherein thecancer is prostate cancer.
 3. The method as described in claim 1,wherein R³ is —H.
 4. The method as described in claim 3, wherein R² isphenyl which may be substituted with halogen, lower alkyl, or —OR⁰. 5.The method as described in claim 4 or a pharmaceutically acceptable saltthereof, wherein R⁴ is —N(R⁰)-lower alkylene-(aryl or heteroaryl, whichmay each be substituted), or —N(R⁰)—O-lower alkylene-(aryl orheteroaryl, which may each be substituted).
 6. The method as describedin claim 5, wherein R¹ is (lower alkylene)-OH or substituted cycloalkyl{wherein said lower alkylene may be substituted with a member selectedfrom the group consisting of —OH and phenyl (which may be substitutedwith halogen, lower alkyl, or —OR⁰), and said substituted cycloalkyl issubstituted with a member selected from the group consisting of —OR⁰,—N(R⁰)₂, —N(R⁰)C(O)R⁰, —N(R⁰)-lower alkylene-OR⁰, —N(R⁰)S(O)₂-loweralkyl and heterocyclic group}.
 7. The method according to claim 1,wherein the compound is(4-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenyl)aceticacid, or a pharmaceutically acceptable salt thereof.